Article

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

April 2006
Gut 55(4):529-35

April 2006
55(4):529-35

DOI:10.1136/gut.2005.069674

Source
PubMed

Authors:

Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and non-obese subjects with chronic HCV. A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index > or = 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

SOCS3 mRNA expression and polymorphisms as pretreatment predictor of response to HCV genotype 3a IFN-based treatment

Article

Full-text available

Dec 2016

AimSuppressor of Cytokine Signaling 3 (SOCS3) gene belongs to SOCS family as one of the negative regulators of cytokine signaling and IFN response that function via the JAK-STAT pathway in antiviral response. SOCS3 expression and genetic polymorphism influences the pathogenesis and outcome of antiviral treatment in hepatitis C virus (HCV) infected patients. This study was designed for analysis of SOCS3 gene expression and polymorphism in Pakistani HCV patients. Methods This descriptive study was conducted on 250 diagnosed HCV genotype 3a infected subjects. The study population was divided into two major groups on the basis of therapeutic response i.e. sustained virological response (SVR) and non-responders/relapsers (NR). SOCS3 gene mRNA expression analysis was done by using Real time PCR technique, whereas ARMS PCR technique was used for analysis of SOCS3 gene polymorphisms i.e. 8464 A/C (rs12952093), −4874 A/G (rs4969170) and −1383 A/G, (rs4969168). ResultsGene expression analysis of SOCS3 showed that there was statistically significant increase of 2.275-fold and 3.72-fold in relative gene expression for SVR and NR as compared to normal healthy samples (p < 0.001). The distribution of rs4969168, rs4969170 and rs12952093 genotype frequencies between SVR versus NR group were not statistically significant, only the allelic frequency of rs4969170 was statistically significant (p ≤ 0.0001) with therapeutic response. Conclusion The gene expression analysis of SOCS3 showed a clear difference in mRNA expression of SOCS3 as a possible indicator of therapeutic response rather than polymorphism of SOCS3 gene in our studied population.

Hepatitis C virus infection in vitro triggers endoplasmic reticulum stress and downregulates insulin receptor substrates 1 and 2 through upregulation of cytokine signaling suppressor 3

Article

Full-text available

Jan 2014

Hepatitis C virus (HCV) infection is highly prevalent worldwide and most of HCV infections enter into chronic phase subsequently leading to insulin resistance (IR) and clinical complications. Although the clinics of chronic HCV infection is well described, there is need to better understand the molecular mechanisms of HCV-induced IR. Therefore this study was aimed to unveil the role of host genes involved in the development of HCV-induced IR. For this purpose the expression of selected genes in HCV-infected and non-infected Huh-7 cells at various time post infection (p.i.) was assayed by real-time PCR. HCV infection was found to trigger endoplasmic reticulum (ER) stress response as demonstrated by an increase in the expression of calreticulin (Cal) gene but no change in the expression of Gadd153 gene. The infection also enhanced the expression of suppressor of cytokine signaling 3 (SOCS-3), responsible for the degradation of insulin receptor substrates (IRS). Moreover, it led to a decreased expression of key signaling molecules IRS-1 and IRS-2, unchanged expression of SOCS-7 and increased expression of downstream signaling molecule Akt. Altogether these findings indicate that the HCV infection induces ER stress and IR in Huh-7 cells in vitro.; phone: +92-51-9085-6147. Abbreviations: HCV = hepatitis C virus; IFN = interferon; IR = insulin resistance; Cal = calreticulin; Gadd153 = growth arrest and DNA damage-inducible protein; SOCS = suppressor of cytokine signaling; IRS = insulin receptor substrate; ER = endoplasmic reticulum; Akt = ser-ine/threonine kinase or protein kinase B; p.i. = post infection

Control of progression towards liver fibrosis and hepatocellular carcinoma by SOCS3 polymorphisms in chronic HCV-infected patients

Article

Aug 2018

Background & aims Chronic Hepatitis C is one of the most important risk factors of liver cirrhosis and hepatocellular carcinoma. Before reaching these ultimate steps, insulin resistance triggered by hepatitis C virus infection is known to participate in the progression of liver disease. The present study aims to investigate the influence of two functional polymorphisms on SOCS3 mRNA expression and on the outcomes of CHC progression in a North African context. Patients & methods In this case-control study, 601 Moroccan subjects composed of 200 healthy controls, 101 resolvers and 300 patients with persistent HCV infection including 95 mild chronic hepatitis, 131 Advanced Liver Diseases and 74 HCC were enrolled. They were genotyped for the 4874 A/G (rs4969170) and A + 930– > G (rs4969168) SOCS3 variants using TaqMan SNPs assays. SOCS3 mRNA expression was assessed using Real Time PCR technique. Results Logistic regression analysis showed that variation at rs4969168 was associated with spontaneous clearance of HCV (P < 0.05). In addition, minor allele frequencies were significantly higher in AdLD patients when compared to the mCHC group both for rs4969168 (P = 7.0 E-04) and rs4969170 (P = 4.0 E-05). A significant association between haplotype and liver disease progression was also found. Moreover, SOCS3 mRNA was significantly more expressed in peripheral leukocytes from patients with HCC than in those from mCHC. Finally, rs4969170 was significantly associated with LDL-lipoprotein (P = 0.04), total cholesterol (P = 5.0 E-04), and higher fasting glucose levels (P = 0.005) in patients with persistent HCV infection. Conclusions Our results underline the importance of the functional SOCS3 polymorphisms in the modulation of CHC progression and suggest their contribution to HCC development by affecting its mRNA expression and perturbing key metabolic parameters.

Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity

Article

Full-text available

Feb 2017
INFLAMMATION

Obesity provokes an imbalance in the immune system, including an aberrant type I interferon response during some viral infections and after TLR stimulation. SOCS3 overexpression and altered systemic leptin levels could be responsible for the reduced type I interferon production in people with obesity and, eventually, significantly increase the risk of viral infection. The aim of this study was to determine whether SOCS3- and leptin-induced tolerance are responsible for the reduced type I interferon production in people with obesity. SOCS3 overexpression in PBMCs from people with obesity was inhibited with the small interfering RNA (siRNA) assay, and leptin-induced tolerance was evaluated in PBMCs from non-obese volunte\ers and U937 cells treated with TLR ligands. SOCS3, but not SOCS1, gene silencing via siRNA increased the type I interferon response in PBMCs obtained from people with obesity. On the other hand, leptin induced SOCS3 expression and inhibited type I interferons in PBMCs from healthy donors and in U937 monocytes stimulated with TLR ligands. Taken together, these results demonstrate that reduced type I interferon production in obesity is caused by SOCS3 overexpression as well as tolerance induced by leptin. Here, we demonstrate a key role of leptin and SOCS3 in inhibiting the type I interferon response during obesity.

Impact of Weight Loss in Overweight Patients Enrolled in Weight Management Program Prior to Hepatitis C Treatment on Early Virological Response

Article

Full-text available

Jan 2016

The role of SOCS proteins in the development of virus- induced hepatocellular carcinoma

Article

Full-text available

Apr 2021
VIROL J

Background Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host’s antiviral responses to achieve persistent infection. Conclusions This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.

LncRNAs in HCV Infection and HCV-Related Liver Disease

Article

Full-text available

Jan 2020

Long non-coding RNAs (lncRNAs) are transcripts with poor coding capacity that may interact with proteins, DNA, or other RNAs to perform structural and regulatory functions. The lncRNA transcriptome changes significantly in most diseases, including cancer and viral infections. In this review, we summarize the functional implications of lncRNA-deregulation after infection with hepatitis C virus (HCV). HCV leads to chronic infection in many patients that may progress to liver cirrhosis and hepatocellular carcinoma (HCC). Most lncRNAs deregulated in infected cells that have been described function to potentiate or block the antiviral response and, therefore, they have a great impact on HCV viral replication. In addition, several lncRNAs upregulated by the infection contribute to viral release. Finally, many lncRNAs have been described as deregulated in HCV-related HCC that function to enhance cell survival, proliferation, and tumor progression by different mechanisms. Interestingly, some HCV-related HCC lncRNAs can be detected in bodily fluids, and there is great hope that they could be used as biomarkers to predict cancer initiation, progression, tumor burden, response to treatment, resistance to therapy, or tumor recurrence. Finally, there is high confidence that lncRNAs could also be used to improve the suboptimal long-term outcomes of current HCC treatment options.

Safety and efficacy of direct-acting antivirals for chronic hepatitis C in patients with chronic kidney disease

Article

Full-text available

Jan 2020
BMC Nephrol

Background: This is a real-world evidence study that aims to analyze the efficacy, tolerability and safety profile of paritaprevir/ombitasvir/ritonavir and dasabuvir, in patients with renal impairment. Methods: We conducted an observational prospective study, on 232 patients with chronic kidney disease, undergoing treatment with paritaprevir/ombitasvir/ritonavir and dasabuvir, for chronic hepatitis C infection - genotype 1b. Renal and liver function were assessed at the beginning of therapy, monthly during treatment and three months after therapy completion. Results: All patients achieved sustained virologic response. Common side effects were nausea, fatigue and headache. Close monitoring of tacrolimus blood levels and dose reduction was required in kidney transplant recipients. Conclusions: HCV therapy in the setting of renal dysfunction has always been a challenging topic. Direct-acting antivirals have shown promising effects, demonstrating good tolerance and efficacy in patients with HCV infection and renal impairment. Sustained virologic response within our study population was 100%.

Fisiopatología de la hepatitis C y diabetes mellitus. Hacia la cura de dos epidemias en el siglo XXI

Article

Full-text available

Oct 2019

La infección crónica por virus de la hepatitis C (VHC) y la diabetes mellitus (DM) son dos problemas de salud pública que impactan los sistemas de salud, con una alta carga económica global. La infección por VHC produce manifestaciones hepáticas tales como hepatitis, cirrosis y carcinoma hepatocelular; asimismo, se ha involucrado en la patogénesis de manifestaciones extrahepáticas, entre las cuales se ha asociado con alteraciones metabólicas como la DM. Estudios longitudinales y transversales han reportado mayor incidencia y prevalencia de DM en pacientes con infección crónica por VHC. La DM acelera la progresión histológica y clínica en pacientes con infección crónica por VHC y las complicaciones cardiovasculares. Recientemente se ha avanzado en el tratamiento y la introducción de nuevos medicamentos como los antivirales de acción directa, que mejoran el control glucémico en estos pacientes.

A significant upsurge of body mass index in patients with chronic hepatitis C successfully treated with direct-acting antiviral regimens

Article

Full-text available

Aug 2019
TURK J GASTROENTEROL

Background/aims: There is less data regarding the changes in body mass index (BMI) after treating hepatitis C virus (HCV) patients with new direct-acting antiviral agents (DAAs). This study aimed to assess the changes in BMI in chronic HCV patients treated with DAAs in Egypt and to explore other factors influencing this change. Materials and methods: The data of chronic HCV patients who received antiviral therapy with new DAAs in one of Egypt's specialized viral hepatitis treatment centers were retrospectively analyzed. In addition to the routine clinical and laboratory workup, changes in body weight during and after treatment were monitored and BMI was calculated. Viral load was measured at 12 weeks post-treatment to assess a sustained virological response. Patients with documented thyroid abnormalities, bariatric surgery, or ensuing special diets were excluded. BMI of >30 was taken as the cutoff for pa¬tients with obesity. Results: The study included 162 patients with a mean age of 48.56±11.49 years, of whom 61.1% were males, 16% were treatment-experienced, 12% were diabetic, and 29% were obese. Treatment duration was 12 weeks in 84% of patients and 24 weeks in 16% of patients. There was a significant increase in BMI post-treatment as compared to pretreatment measures (28.68±5.35 vs 28.18±4.55) (p=0.03). BMI changes were constant regardless of cirrhosis or previous treatment experience. Conclusion: Treatment of chronic HCV with DAAs was associated with increased body mass index. Further studies are needed to explore if this effect is secondary to treatment with DAAs or is an improvement in the liver function and lifestyle of treated patients.

The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)‐α via signal transducer and activator of transcription (STAT)3 and extracellular signal‐regulated kinase (ERK)–mediated induction of suppressor of cytokine signaling (SOCS)3

Article

Full-text available

Jun 2019
FASEB J

Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF‐α‐mediated inflammatory responses. However, the mechanism by which HCV up‐regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7′s ion channel activity was required for optimal up‐regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase–signal transducer and activator of transcription (JAK‐STAT) and MAPK pathways were required for p7‐mediated induction of SOCS3. HCV‐p7 expression suppressed TNF‐α‐mediated IκB‐α degradation and subsequent NF‐κB promoter activity, revealing a new and functional, anti‐inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV‐p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF‐α, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.—Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)‐α via signal transducer and activator of transcription (STAT)3 and extracellular signal‐regulated kinase (ERK)–mediated induction of suppressor of cytokine signaling (SOCS)3. FASEB J. 33, 8732–8744 (2019). www.fasebj.org

Metabolic syndrome and non-alcoholic fatty liver disease in post-transplant patients affected by hepatitis C virus (genotype 1)

Article

Full-text available

Jul 2010

A Severe Case of Hyperglycemia in a Kidney Transplant Recipient Undergoing Interferon-Free Therapy for Chronic Hepatitis C

Article

Full-text available

Oct 2018

Laura Iliescu

Context: Hepatitis C and diabetes represent important health problems globally. The new-onset diabetes after transplantation is a particular entity that appears due to the use of immunosuppression among transplanted patients. Objective: We aim to describe the clinical and biological aspects of severe hyperglycemia in a kidney transplant recipient undergoing Interferon-free therapy for chronic hepatitis C, discussing the interference of different factors with the glucose metabolism. Design: The occurrence of diabetes in a patient with history of renal transplantation and Interferon-free treated hepatitis C was studied from both clinical and paraclinical points of view. Subjects and methods: When presenting to the hospital, extensive blood tests were performed on the patient, revealing significant hyperglycemia and an elevated level of blood tacrolimus. Creatinine clearance was calculated. ECG presented T-wave alterations. Intensive insulin protocol was applied, the case being managed in a multidisciplinary approach. Results: Blood glucose and tacrolimus were slowly normalized, under therapy. The antiviral treatment was continued, with the achievement of sustained virologic response. Conclusions: Diabetes mellitus can have many causes, hepatitis C and transplantation both having an impact on glucose metabolism. The association of the three entities should be carefully managed, due to its enhancing effect on morbidity and mortality.

First-wave protease inhibitors for hepatitis C genotype 1 treatment: A real-life experience in Brazilian patients

Article

Full-text available

Apr 2018
REV SOC BRAS MED TRO

Introduction: Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. Methods: A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. Results: A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. Conclusions: In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.

Impact of Direct Acting Antivirals for Treatment of Chronic Hepatitis C Virus Infection on Glycemic Control in Egyptian Patients with Type 2 Diabetes Mellitus

Article

Jan 2018

Background: hepatitis C virus (HCV) infection looks to increase the probability of incidental type 2 diabetes mellitus in predisposed subjects, unrelated to the stage of liver disease. The processes through which hepatitis C triggers T2DM include direct effects of HCV, insulin resistance, proinflammatory cytokines and other immune-induced mechanisms.

Regulation of the Interferon Response by lncRNAs in HCV Infection

Article

Full-text available

Feb 2018

The interferon (IFN) response is a critical component of the innate immunity antiviral pathways in mammalians. IFN signaling results in increased expression of cellular factors that block key steps in the viral replication cycle. Many IFN-induced antiviral factors act through decreasing viral entry, replication, transcription, translation, packaging and release. However, these effects are also deleterious for the viability of the cell, which necessitates a tight control over the magnitude and duration of the IFN response. This is partially achieved through the IFN-mediated activation of negative regulatory factors that help in termination of the IFN response and return to a normal homeostatic state. Such built-in negative regulatory mechanisms are frequently hijacked by viruses such as the Hepatitis C virus (HCV) to increase viral replication and productive infections. We and others have shown that long non-coding RNAs (lncRNAs) play prominent roles in regulation of the IFN response. Activation of the IFN cascade alters the expression of a large number of lncRNAs, many of which are directly induced by the JAK/STAT pathway and thus, resemble the well-studied protein-coding interferon-stimulated genes (ISGs). While only a handful of IFN- and virally induced lncRNAs have been characterized, recent studies have identified several lncRNAs that act as positive or negative regulators of expression of ISGs during the IFN response. A number of such regulatory lncRNAs have multiple ISG targets, while others act on a single neighboring ISG. Another group of studied lncRNAs act further upstream and regulate the expression of IFN genes or factors that sense the presence of viral genome or replication products. The large number of unstudied IFN- and virally induced lncRNAs makes it highly likely that future studies will reveal a much greater share for this class of transcripts in regulation of the antiviral response. In addition to their physiological roles, the expression of such lncRNAs is frequently modulated by virally encoded factors to interfere with the antiviral response and promote viral replication, thus making them ideal targets for therapeutic intervention.

Role of Interleukin 28B Polymorphisms in Response to Interferon Based Therapy for Hepatitis C Virus Clearance

Article

Full-text available

Jan 2018

Background: Interleukin-28B (IL28B) locus on a human chromosomal region mapped to 19q13 execute immune defense against viruses. During Hepatitis C Virus (HCV) infection the IL28B has a promising role in deciding the consequence of infection for spontaneous clearance of viruses or causing chronic liver infection. Treatment of chronic hepatitis C includes use of direct acting antivirals, Pegylated-Interferon (PEG-IFN) and Ribavirin (RBV) therapy. Also, interferon free regimens are suggested to be useful in resistant patients. Numerous reports including Genome-Wide Association Studies (GWAS), comprehensive meta-analysis and independent case-control studies in different population have revealed the association between certain Il-28B polymorphisms and response to the PEGIFN- RBV therapy in patients infected with HCV. Method: We searched all peer-reviewed relevant and recent literature manually for the present review. Conclusion: The GWAS studies have revealed an important role of IL28B in HCV infection, which was supported by many independent studies and meta-analysis by different groups in different ethnicities. IL28B genotyping may be use as predictors of response for IFN-based therapy and personalized treatment of hepatitis C patient.

Improved Insulin Resistance with Clearance of Chronic Hepatitis C, Genotype 4

Article

Full-text available

Mar 2010

Insulin Resistance in Patients with Chronic Hepatitis C

Article

Full-text available

Jun 2016

Introduction. Insulin resistance is the most common extrahepatic manifestation associated with hepatitis C virus, which leads to developing more pronounced fibrosis and liver steatosis. The aim of the study was to assess the prevalence of insulin resistance in non-diabetic, treatment naive patients with chronic hepatitis C and to analyze the relation of insulin resistance with genotype, viral load, gender, age, laboratory parameters, inflammatory and fibrotic changes in the liver, body mass index (BMI) and the presence of steatosis. Methods. In this cross sectional study, 224 patients with hepatitis C viral infection were included. The patients were divided into two groups. The first group was with no insulin resistance and the second one with present insulin resistance. They were compared in terms of genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, BMI and liver steatosis. Results. Insulin resistance was present in 45.5% of patients. The following factors were associated with insulin resistance: age (p=0.0022), inflammatory and fibrotic changes in the liver (p=0.001, p=0.006, respectively), steatosis (p=0.015) and transaminase activities (for AST, p=0,002, for ALT, p=0.001). Conclusion. In the Republic of Macedonia, a high percent of 45.5% among non-diabetic and treatment naïve patients with chronic viral hepatitis C, had insulin resistance. Insulin resistance was more prevalent in older patients, in those with more pronounced inflammatory and fibrotic changes in the liver, in patients with steatosis and in those with higher transaminase activity.

Factors Associated with Improved Glycemic Control by Direct-Acting Antiviral Agent Treatment in Egyptian Type 2 Diabetes Mellitus Patients with Chronic Hepatitis C Genotype 4

Article

Full-text available

Aug 2017

Background: The association of chronic hepatitis C virus (HCV) infection with type 2 diabetes mellitus (T2DM) was first reported in 1994. Little is known about the effect of direct-acting antiviral agents (DAAs) on glycemic control in T2DM patients. The aim of the present study was to evaluate the factors associated with improved glycemic control (IGC) by DAA treatment in Egyptian T2DM patients with chronic HCV genotype 4 infection. Methods: This study included 460 T2DM patients with chronic HCV genotype 4 infection. Four hundred patients received DAAs and 60 patients did not receive DAAs. Patients with sustained virological response after 3 months of DAAs (378 patients) were allocated into two groups: first group included 292 patients (77.2%) with IGC and second group included 86 patients (22.8%) with non-improved glycemic control (NIGC). Results: In IGC group, 78 patients (26.7%) needed to decrease the dose of antidiabetic treatment. There were no significant differences between IGC and NIGC groups as regards age, sex, and body mass index. The percentage of patients with positive family history of T2DM, those with Child B class and duration of T2DM were significantly higher in NIGC group compared to IGC. Conclusion: Diabetic patients receiving DAAs should be closely monitored for reduction of antidiabetic drugs especially insulin and sulfonylurea to avoid hypoglycemic events. Improvement of glycemic control with DAAs is more in patients without family history of T2DM, short duration of diabetes mellitus, and mild liver disease.

Supplementary Material

Data

Full-text available

Feb 2017

Successful Withdrawal of Insulin Therapy After Post-Treatment Clearance of Hepatitis C Virus in a Man with Type 2 Diabetes

Article

Full-text available

Apr 2017

Patient: Male, 55 Final Diagnosis: Hepatitis C Symptoms: Icterus Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic Objective Unusual clinical course Background Chronic hepatitis C virus (HCV) infection is associated with increased insulin resistance and risk of type 2 diabetes. Successful antiviral treatment can improve insulin resistance and allow a reduction in blood glucose-lowering treatment. There have been case reports of a reduced insulin requirement in this situation, although 1 case in which insulin was stopped exhibited a subsequent deterioration in glycemic control. Case Report A 55-year-old Italian man was diagnosed with HCV infection in 2000 at the age of 39 years and with type 2 diabetes 6 years later. He was started on metformin but progressed to multiple daily insulin injections after 3 years. He was treated with pegylated interferon, ribavirin, and telaprevir over 12 months from early 2013, and achieved a sustained virologic response and normalization of hepatic function within 6 months of starting therapy. He was subsequently able to reduce his insulin doses from 0.56 to 0.44 U/kg/day over the next 2 years and, based on a random serum C-peptide of 1.73 nmol/L (fasting reference range 0.37–1.47 nmol/L) in the presence of serum glucose 7.9 mmol/L (143 mg/dL) and negative glutamic acid decarboxylase antibodies, he accelerated withdrawal and stopped insulin 6 months later. He is currently taking linagliptin 5 mg daily with good glycemic control. His body mass index and HbA1c have remained <25 kg/m² and <6.0% (<42 mmol/mol), respectively, throughout. Conclusions This case shows that complete withdrawal of long-term insulin therapy may be possible after HCV treatment has induced a sustained virologic response.

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Article

Full-text available

Jan 2017

Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

Successful Hepatitis C Antiviral Therapy Induces Remission of Type 2 Diabetes: A Case Report

Article

Full-text available

Oct 2015

Background: Type 2 diabetes is a well described extra-hepatic manifestation of hepatitis C infection (HCV). Eradication of HCV has led to improvements in insulin resistance but to date has not been shown to induce remission of diabetes. Case report: We report a case of a 49-year-old man with HCV and a 2-year history of T2DM on oral agents. He was initially treated with peg-interferon/ribavirin (peg-IFN/rib) but did not achieve a HCV treatment response. Four years later he was retreated with peg-IFN/rib plus an HCV protease inhibitor (boceprevir). His HbA1c at the start of treatment was 7.9%. Antiviral response to HCV-therapy correlated with a significant improvement in glucose control without a change in diabetes therapy or improvement in adherence. He achieved a sustained virological response and within a year of completing antiviral therapy he no longer required medical therapy for diabetes. Two years after the completion of HCV treatment, the patient has maintained an HbA1c of 5.8% without any diabetes medications. Conclusions: This case provides evidence of the important relationship between HCV and diabetes and highlights the potential reversibility of glucose abnormalities with successful eradication of HCV. Increased awareness of this association may improve detection of undiagnosed HCV infection, identify patients with reversible causes of diabetes, guide therapeutic decisions for HCV treatment, and improve outcomes in patients with both diseases.

Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: Study protocol for a randomized controlled trial

Article

Full-text available

Jul 2016
TRIALS

Background Approximately 180 million people worldwide, (3 % of the world’s population) are infected with hepatitis C (HCV). Insulin resistance (IR) and type 2 diabetes (T2DM) are common extrahepatic manifestations of chronic HCV infection and associated with poor treatment and liver-related outcomes. The presence of these metabolic complications have been associated with poor response to interferon-based HCV antiviral therapy and increased risk of liver-related outcomes. Metformin, an insulin sensitizer is known to improve HCV treatment response and has been associated with a reduced risk of developing hepatocellular carcinoma (HCC). This study will evaluate the effect of metformin on preventing progression or promoting regression of liver fibrosis, rate of virologic cure (SVR) and other metabolic measures in HCV-HIV co-infected and HCV mono-infected study participants who have IR and are planning on initiating HCV treatment. Methods This study is a prospective 48-week single-centre, randomized, open-label, controlled trial of HIV-HCV co-infected and HCV mono-infected patients with IR (HOMA-IR ≥ 2.0) who are planning to initiate HCV antiviral therapy. Sixty participants will be recruited from The Ottawa Hospital Viral Hepatitis Clinic. Participants will be randomized in a 1:1 ratio to either arm 1, metformin 2 g (1 g twice daily) plus lifestyle, or to arm 2, lifestyle alone. The primary outcome will be the change in FibroScan® score (kPa) from baseline to week 12 (start of HCV treatment), the end of HCV treatment (week 24) and 24 weeks post HCV treatment (week 48). Secondary outcomes include changes in liver fibrosis using AST to platelet ratio index, changes in glucose and lipid levels, anthropometric measures, changes in alpha-fetoprotein levels, patient acceptability, and changes in dietary and physical activity parameters. Discussion This pilot study will be the first to evaluate the role of metformin on liver fibrosis in HCV-HIV co-infected and HCV mono-infected patients with IR receiving DAA HCV treatment. If metformin is effective in reducing liver fibrosis in this patient population, this will represent a well-tolerated, easy-to-administer, inexpensive therapy that will protect against negative HCV outcomes. This study will also be an opportunity to evaluate the impact of insulin resistance and hyperglycemia on viral clearance in HCV-infected patients treated with interferon-free regimens. Trial registration ClinicalTrials.gov NCT02306070 version 4.0 (June 29, 2015) Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1454-6) contains supplementary material, which is available to authorized users.

Markedly Improved Glycemic Control in Poorly Controlled Type 2 Diabetes following Direct Acting Antiviral Treatment of Genotype 1 Hepatitis C

Article

Full-text available

Jan 2016

Type 2 diabetes mellitus (T2DM) is often associated with hepatitis C virus (HCV) infection. Successful HCV treatment may improve glycemic control and potentially induce remission of T2DM. We report a case of an obese 52-year-old woman with mixed genotype 1a/1b HCV infection with compensated cirrhosis and a 10-year history of poorly controlled T2DM on insulin therapy. Following successful therapy with sofosbuvir, simeprevir, and ribavirin, her insulin requirements decreased and her glycosylated hemoglobin (HgA1c) normalized despite weight gain. This case suggests an association between HCV and T2DM and the potential for significant improvement in glycemic control with eradication of HCV.

Personality, Coping, and Well-Being for People Living with Chronic Hepatitis C

Article

Apr 2016

The present study examined the relationships between personality, coping strategies, and health ratings to extend past research to people living with chronic hepatitis C (HCV). Participants were 35 people (11 men, 24 women; M age = 49.6 yr., SD = 10.6) living with chronic hepatitis C for an average of 9.0 yr. (SD = 6.0) since diagnosis. Participants provided descriptions of stressful situations and responded to a personality inventory, Ways of Coping Questionnaire scales (planful problem solving and escape-avoidance) and SF36 Health Survey scales measuring physical functioning and mental health. The stressful situations were judgmentally clustered into seven dimensions (diagnosis/mortality, disclosure, stigma, social and work role functioning, compounding problems, and no stress). Correlational analyses indicated strong negative relationships between escape–avoidance coping and health measures. Emotional Stability and Extraversion were positively related to both health variables, and Extraversion was negatively related to escape–avoidance coping. The results suggest that research from other contexts that has examined these relationships tended to generalize to people living with HCV.

Host restriction factors for hepatitis C virus

Article

Full-text available

Jan 2016
WORLD J GASTROENTERO

Host-hepatitis C virus (HCV) interactions have both informed fundamental concepts of viral replication and pathogenesis and provided novel insights into host cell biology. These findings are illustrated by the recent discovery of host-encoded factors that restrict HCV infection. In this review, we briefly discuss these restriction factors in different steps of HCV infection. In each case, we discuss how these restriction factors were identified, the mechanisms by which they inhibit HCV infection and their potential contribution to viral pathogenesis.

Kinetic response of wild and mutant core codon 70 strains of HCV genotype 1b to pegylated interferon-α and ribavirin therapy

Article

Full-text available

Dec 2015
VIROL J

Background: Amino acid (aa) 70 substitution (R70Q/H) in the core protein of hepatitis C virus (HCV) genotype 1b has been shown to be one of the key factors in determining resistance for pegylated interferon-α plus ribavirin combination therapy (PEG-IFNα/RBV). But the exact mechanisms remain unclear. The aim of this study was to investigate the dynamic response of wild and mutant core codon 70 strains to PEG-IFNα/RBV treatment. Methods: One hundred twelve Chinese patients with chronic HCV 1b infection were enrolled and received a standard protocol of 48 weeks of PEG-IFNα/RBV therapy and 24 consecutive weeks of follow-up. Serial blood samples were obtained at pretreatment baseline, and again at weeks 2, 4, 8, 12, and 24 during therapy for the quantification of 70R and 70Q/H strains. Dynamic characteristics and association with early virological response (EVR), sustained virological response (SVR) and IL28B genotypes were analyzed. Results: Of the 112 patients enrolled in this study, 93.8 % (105/112) were infected with mixture of 70R and 70Q/H strains before treatment. The 70Q/H strain was dominant in 20.5 % of patients. 42.9 % of patients with dominant 70Q/H exhibited EVR versus 88.6 % of patients with dominant 70R (P < 0.001). Furthermore, 35.0 % of patients with dominant 70Q/H exhibited SVR versus 77.4 % with dominant 70R (P < 0.001). However, regardless of the dominant strain, virological response types or the IL28B SNP genotypes, 70Q/H strains always exhibited the same response to treatment as the 70R strains and the percentage of HCV harboring the 70Q/H substitution did not change significantly during treatment. Conclusions: Although the ratio of 70Q/H to 70R is related to the virological response, 70Q/H strains always exhibited the same response as the 70R strains during PEG-IFNα/RBV treatment. Substitution of R70Q/H alone is not enough to lead to resistance to therapy. Positive selection for 70Q/H induced by IFNα was not observed.

Can laboratory parameters be predictive factors for treatment effectiveness of patients suffering from viral hepatitis C?

Article

Full-text available

Jul 2015

Wstęp Złotym standardem terapii przewlekłego wirusowego zapalenia wątroby typu C (PWZW-C) w naszym kraju jest terapia skojarzona pegylowanym interferonem alfa (PEG-If-α) i rybawiryną. Celem pracy była ocena różnic w wartościach poszczególnych parametrów morfologii krwi obwodowej oraz wyników badań biochemicznych w toku leczenia chorych z PWZW-C, u których osiągnięto i nie osiągnięto trwałej odpowiedzi wirusologicznej ( sustained virologic response – SVR). Materiał i metody 51 chorych (25 kobiet i 26 mężczyzn, średnia wieku 48,7 ± 12,8 roku) zakażonych genotypem 1b wirusa HCV podzielono na dwie grupy: pierwszą stanowili chorzy (41,2%) których terapia zakończyła się osiągnięciem SVR [SVR(+)], drugą stanowili pozostali chorzy [SVR(-)]. Przed rozpoczęciem terapii oraz po 12, 24, 48 tygodniach od rozpoczęcia, a następnie po 24 tygodniach od zakończeniu leczenia oceniano: stężenie hemoglobiny, hematokryt, liczbę erytrocytów, leukocytów oraz płytek krwi, aktywność aminotransferazy asparaginianowej (AspAT), aminotransferazy alaninowej (AlAT), fosfatazy alkalicznej (ALP) oraz gamma-glutamylotranspeptydazy (GGTP), stężenie glukozy, bilirubiny, kreatyniny, kwasu moczowego, fT3, fT4, TSH, białka C-reaktywnego (CRP). Analizę statystyczną przeprowadzono przy użyciu testów: ANOVA Friedmana, U Manna-Withneya oraz t-Studenta. Wyniki Aktywność AspAT, AlAT w grupie była niższa w grupie SVR(+) od 12 tygodnia aż do 72 tygodnia. Aktywność GGTP była znamiennie niższa w grupie SVR(+). Spadek stężenia TSH w 12 tygodniu oraz wzrost stężenia fT4 w 24 tygodniu leczenia był wyraźniejszy u osób SVR(+). Hematokryt osiągnął niższe wartości w grupie SVR(+) w 48 tygodni od włączenia i 24 tygodnie po zakończeniu terapii. Wnioski Chorzy leczeni z powodu PWZW-C rzadziej osiągają SVR w przypadku podwyższonej aktywności GGTP przed rozpoczęciem leczenia i utrzymywania się zwiększonej aktywności aminotransferaz w trakcie terapii. Korzystny wpływ może mieć utajona nadczynność tarczycy.

The immune response in chronic HBV infection

Article

Jun 2024
J VIRAL HEPATITIS

Antonio Bertoletti

Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV‐host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.

Diabetes and Liver Disease

Chapter

Nov 2019

The prevalence of diabetes is rising in the United States, with a similar increase in associated complications. Diabetes has significant deleterious effects on many organ systems including the liver. Hepatic complications include the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatocellular carcinoma, liver failure, and the onset of diabetes following liver transplantation. There is significant morbidity and mortality associated with these conditions. Understanding the clinical characteristics and pathophysiology of diabetes related liver disease affords care providers an opportunity to prevent, monitor, and treat these complications. In order to successfully impact clinical outcomes the specific treatment of hepatic disorders must be coordinated with the management of underlying diabetes. While limited treatments currently exist, new therapeutic modalities are being developed that target insulin resistance, cytokine induced injury, and fatty acid metabolism.

Women are from venus: implications for diversified sex-based preexposure prophylaxis approaches

Article

Aug 2021
AIDS

The Impact of Host Factors on Management of Hepatitis C Virus

Article

Apr 2012

Morbid obesity and hepatitis C: treat as normal or are there additional issues to consider?

Chapter

Mar 2020

Obesity has been considered an independent risk factor for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis and was significantly associated with metabolic disorders, tissue inflammation, and liver fibrosis. Obesity is also associated with an increased risk of hepatocellular carcinoma. Development of direct‐acting antiviral drugs targeting viral proteins has revolutionized the treatment of chronic hepatitis C. Liver fibrosis as a consequence of hepatic stellate cell activation remains after sustained virologic response (SVR), mainly in patients with advanced fibrosis and/or severe comorbidities in the era of interferon therapies. The identification of biomarkers able to predict outcomes in obese patients with hepatitis C after SVR and the development of drugs able to reverse hepatic stellate cell activation are two major unmet needs in this field.

Suppressors of Cytokine Signaling and Protein Inhibitors of Activated Signal Transducer and Activator of Transcriptions As Therapeutic Targets in Flavivirus Infections

Article

Aug 2019
J INTERF CYTOK RES

Flaviviruses cause significant human diseases putting more than 400 million people at risk annually worldwide. Because of migration and improved transportation, these viruses can be found on all continents (except Antarctica). Although a majority of the viruses are endemic in the tropics, a few [West Nile virus (WNV) and tick-borne encephalitis virus (TBEV)] have shown endemicity in Europe and North America. Currently, there are vaccines for the Yellow fever virus, Japanese encephalitis virus, and TBEV, but there is no effective vaccine and/or therapy against all other flaviviruses. Although there are intensive efforts to develop vaccines for Zika viruses, dengue viruses, and WNVs, there is the need for alternative or parallel antiviral therapeutic approaches. Suppressors of cytokine signaling (SOCS) and protein inhibitors of activated signal transducer and activator of transcription (STATs; PIAS), both regulatory proteins of the Janus kinase/STAT signaling pathway, have been explored as therapeutic targets in herpes simplex and vaccinia viruses, as well as in cancer therapy. In this review, we briefly describe the function of SOCS and PIAS and their therapeutic potential in flaviviral infections.

Expression of SOCS1 and SOCS3 Genes in Interferon-Treated and Direct-Acting Antiviral Drugs-Treated Hepatitis C Patients

Article

Full-text available

Jun 2018
J INTERF CYTOK RES

Genetics of host plays a significant role in susceptibility and pathogenesis of disease. During hepatitis C virus (HCV) infection, HCV proteins interfere with interferon (IFN) signaling pathways and upregulate transcription of suppressor of cytokine signaling 1 and 3 genes (SOCS1 and SOCS3), which results in impaired immune response. In this study, we evaluated relative expression of SOCS1 and SOCS3 in untreated HCV patients and patients treated with 2 different treatment strategies that are, (IFN therapy and direct-acting antiviral (DAA) drug regimen. To study gene expression, peripheral blood mononuclear cells (PBMCs) were isolated by using Histopaque. Total RNA was extracted from PBMCs by using BIOzol. Nine microgram of total RNA from each sample was used and reverse transcribed into single-stranded complementary DNA (cDNA) by using M-MLV reverse transcriptase (Invitrogen). The synthesized cDNA was diluted to a final concentration of 500 ng/μL. This diluted cDNA was further used for expression analysis of SOCS1and SOCS3 genes using Rotor Gene Q Real-Time PCR Detection System (QIAGEN). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified as a housekeeping gene. We found that the SOCS1 expression in IFN and DAA-treated patient groups was 5.4 fold and 1.2 fold, respectively, high compared with the healthy controls (IFN versus healthy, P = 0.019 and DAA versus healthy, P = 0.91), whereas the SOCS3 expression in IFN and DAA-treated patient groups was 3.7 fold and 2 fold, respectively, high in comparison with the expression in healthy controls (IFN versus healthy, P = 0.025 and DAA versus healthy, P = 0.03). We also found a significant difference in the relative expression of SOCS1 and SOCS3 in DAAs-treated and IFN/ribavirin (RBV)-treated and untreated individual. We concluded that by targeting HCV proteins with DAAs, SOCS1, and SOCS3 transcription can be more effectively normalized compared to the treatment with IFN/RBV therapy.

Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C

Article

Full-text available

Dec 2017
Curr Hepat Rep

Purpose of Review Patients with chronic hepatitis C infection frequently develop non-alcoholic fatty liver disease (NAFLD), which confers a risk of hepatocellular carcinoma (HCC). Although direct-acting antivirals allow the majority of patients to achieve a sustained virologic response (SVR), post-SVR patients still carry a non-negligible risk of HCC. This review summarizes recent findings regarding the pathogenesis of hepatitis C virus (HCV)-related NAFLD and its impact on post-SVR patients. Recent Findings The recently discovered HCV-induced steatosis mechanisms include the upregulation of microRNA-27 expression and the formation of HCV-lipoviral particles, which suppress β-oxidation and triglyceride hydrolysis, respectively. Recent studies also revealed the incidence of NAFLD even among post-SVR patients, as well as an association of steatosis with hepatic inflammation and hepatocarcinogenesis. Summary HCV induces changes in microRNA expression and lipoviral particles to directly promote the development of steatosis. In post-SVR patients, NAFLD is an important pathological condition related to hepatic inflammation and hepatocarcinogenesis.

Diabetes and Liver Disease

Chapter

Jan 2017

Hepatitis C virus induces a pre-diabetic state by directly impairing hepatic glucose metabolism in mice

Article

Full-text available

May 2017

Virus-related type-2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV). However, the underlying molecular mechanisms remain unknown. Our aims were to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV-ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes, via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitantly with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV proteins-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce in- sulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a pre-diabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.

Hepatic IFNL4 expression is associated with non-response to interferon-based therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients: IFNL4 and ISG expression in liver

Article

Dec 2016
J MED VIROL

Single nucleotide polymorphisms (SNPs) within or near interferon lambda 4 (IFNL4) gene located upstream of IFNL3 are associated with response to anti-HCV therapy both in interferon (IFN)-based and IFN-free regimens. IFNL4 encodes IFNλ4, a newly discovered type III IFN, and its expression is controlled by rs368234815-TT/ΔG, which is in strong linkage disequilibrium (LD) with other tag SNPs within or near IFNL4 such as rs12979860 and rs8099917. Intrahepatic expression levels of IFN-stimulated genes (ISGs) affect the responsiveness to IFNα and are also associated with IFNL4 genotype. However, IFNL4 expressions and its role in intrinsic antiviral innate immunity remain unclear. This study evaluated the effect of IFNL4 on intrahepatic ISG expression and investigated its relationship with treatment outcomes in liver samples obtained from 49 chronic hepatitis C patients treated with pegylated (PEG)-IFN/ribavirin therapy. IFNL4 mRNA was detected in 11 of 22 patients with IFNL4-unfavorable SNPs but not in patients with favorable genotypes. IFNL4 expression was associated with non-response to PEG-IFN/ribavirin therapy. Intrahepatic expression of antiviral ISGs (ISG15 and MX1) was significantly higher in IFNL4-unfavorable patients with detectable IFNL4 mRNA than in patients with undetectable IFNL4 mRNA, whereas the expression of suppressive ISGs (RNF125, SOCS1, SOCS3, and RNF11) was lower in patients with detectable IFNL4 mRNA. In summary, intrahepatic expression of IFNL4 was associated with increased antiviral ISG expression and decreased suppressive ISG expression at baseline, resulting in poor responsiveness to IFNα-based therapy in HCV infection. This article is protected by copyright. All rights reserved

Diabetes and Liver Disease

Chapter

Jan 2015

Hepatitis B virus X protein impairs α-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A: HBx Upregulates SOCS3 and PP2A

Article

Jul 2016
J MED VIROL

Hepatitis B Virus (HBV) causes liver cirrhosis and hepatocellular carcinoma. Standard therapy includes treatment with interferon (IFN); however, its efficacy is limited. HBV has been reported to impair IFN signaling; however, the mechanism is unclear. Here, the relationship between HBV X protein (HBx) and IFN signaling was investigated by establishing HepG2 cells, stably expressing HBx (HepG2/HBx) via retrovirus-mediated gene transfer. Subsequently, IFN negative-regulator expression and its mechanism were studied. HepG2/HBx cells showed reduced expression of IFN-stimulated genes and expressed higher levels of suppressor of cytokine signaling 3 (SOCS3) and protein phosphatase 2A (PP2A) suppressor compared with control cells. Knockdown of SOCS3 and PP2A restored IFN sensitivity. Moreover, HepG2/HBx cells showed higher phosphorylation levels of signal transducers and activators of transcription 3 and endoplasmic reticulum stress, which are inducers of SOCS3 and PP2A, respectively. Additionally, HBx-knockdown restored IFN sensitivity in HepG2.2.15.7 cells. It was also confirmed that SOCS3 and PP2A expression levels were up-regulated in the liver of patients with HBV infection. The results of this study demonstrated that HBx impairs IFN signaling via increased expression of SOCS3 and PP2A, a novel mechanistic insight, providing a potential therapeutic target to enhance the efficiency of IFN therapy. This article is protected by copyright. All rights reserved.

Fat and viral liver disease

Chapter

Jan 2009

F. Negro

Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus

Article

Apr 2016
CYTOKINE

We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-α) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-α increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-α impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-α. IFN-α-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-α. These results show that IFN-α antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-α, which may be important in better understanding the complex interplay between IFN-α and signal molecules during HCV infection.

Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype I chronic hepatitis C patients: proof of concept

Article

Dec 2011
REV ESP ENFERM DIG

Background: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy. Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells. Methods: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study). Results: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy. Conclusions: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients.

Role of IL28B Gene Polymorphisms in Response to the Standard of Care Treatment in Egyptian Patients with Chronic HCV Genotype Four

Article

Full-text available

Jan 2011

Egypt has the highest prevalence of HCV (predominantly genotype 4) all over the world with 9% countrywide and up to 50% in certain rural areas. Combined PEG-IFN and ribavirin is still the only standard of care treatment in spite of its side effects, high costs and low sustained virological response rates. Hence, this provides a compelling reason for the identification of biomarker predictors of disease response to treatment. Genetic variation in the interleukin 28B (IL28B) genes has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients, however its importance for HCV genotype 4-infected patients is still unevident. This study aimed at assessing whether specific IL28B gene polymorphisms (SNPs), known as rs8099917 and rs12979860 could predict treatment outcomes among chronic HCV genotype4 patients treated with the standard of care treatment. Methods: One hundred of nave chronic HCV patients were selected and submitted to combined interferon/ribavirin therapy, 48% of them have sustained viral response and (SVR) while the remaining 52% failed to respond (non responders). SNPs for rs12979860 and rs8099917 were done by PCR-RFLP technique for all patients before therapy. The CC genotype of rs12979860 was identified in 39 patients, 34 of them (87.2%) achieved SVR, while the CT heterozygous was detected in 51 (51%) patients, 13 of them achieved SVR (25.5%) and the TT was found in 10 patients and only one of them (10%) was responder. The SVR was significantly associated with CC genotypes as compared to other two genotypes (p<0.001), but TT genotype was associated with failed response to therapy. The TT homozygous of rs8099917 genotype was detected in 46 (46%) of overall HCV patients, 37 of them (80.4%) achieved SVR. The GT heterozygous was detected in 42 (42%) of HCV patients, SVR was achieved in 9 (21.4%) of them. While, the GG genotype was found in 12 patients and two of them only (16.7%) were responders. Conclusion: These data suggest that host genetics may be useful for the prediction of treatment outcomes and that IL28B SNP genotype is an important predictive biomarker for SVR in patients with HCV genotypes 4. Further studies based on a larger number of patients are necessary to investigate the present results. [Olfat M Hendy, Elhamy Abd El Moneam, Mona A Al shafie, Maha El-Sabawy, Mohammed A Rady and Sherif A El Baz Role of IL28B Gene Polymorphisms in Response to the Standard of Care Treatment in Egyptian Patients with Chronic HCV Genotype Four. Life Science Journal,. 2011; 8(4): 908-915] (ISSN: 1097-8135). http://www.lifesciencesite.com.

Coadministration of ezetimibe with pegylated interferon plus ribavirin could improve early virological response in chronic hepatitis C obese Egyptian patients

Article

Feb 2016

Background: Ezetimibe has been reported to inhibit viral entry and to reduce BMI and has been proposed as a novel therapeutic agent for chronic hepatitis C (CHC), potentiating the effects of pegylated interferon and ribavirin (peg-IFN/RBV). Objective: The aim of the study was to assess the effects of ezetimibe coadministration with peg-IFN/RBV combination on the early virological response (EVR) rates in nonobese and obese patients with CHC genotype 4 (CHC-4). Patients and methods: A total of 144 CHC-4 patients were divided into two groups; group 1 included nonobese patients (n=76) and group 2 included obese patients (n=68). Each group was further subclassified into equal control and treated groups. The control groups received peg-IFN/RBV combination for 24 weeks, and the treated groups received peg-IFN/RBV plus ezetimibe for 12 weeks and then only peg-IFN/RBV for the remaining 12 weeks. Results: The study revealed that EVR significantly improved in the obese patients (85.3 vs. 64.7% in the treated and control groups, respectively, at P<0.05) without any significant improvement in the nonobese patients. Biochemical responses (defined as normalization of alanine aminotransferase at week 12) were markedly improved in the treated groups in both the nonobese and obese groups compared with their respective controls. Conclusion: The addition of ezetimibe to peg-IFN/RBV combination significantly improves EVR rates in obese patients compared with nonobese patients, and remarkably improves the biochemical responses in both obese and nonobese patients with CHC-4. This may shed light on a new strategy for the treatment of CHC, particularly in obese Egyptian patients.

Suppressor of cytokine signaling 1 expression in peripheral blood mononuclear cells of hepatitis C genotype 1 patients

Article

Full-text available

Jan 2016
J FORMOS MED ASSOC

Background/purpose: While new direct-acting antiviral therapies for hepatitis C virus (HCV) are the standard of care, interferon-α (IFN-α) remains a standard therapy in Taiwan based on its low cost and high response rate to IFN-α-based therapy. IFN-α exerts antiviral activity by inducing the expression of hundreds of genes that establish an antiviral state via Jak kinase (JAK)/signal transducers and activators of transcription (STAT) signaling. We quantified the transcript levels of JAK/STAT signaling genes in peripheral blood mononuclear cells of HCV genotype 1 patients and estimated the correlation between transcript levels and patient responses to IFN-α-based therapy. Methods: A total of 100 HCV genotype 1 naïve patients were enrolled. All patients received response-guided therapy for 24-48 weeks with pegylated IFN-α and ribavirin. Peripheral blood mononuclear cells were collected before treatment. Twenty patients with sustained virological responses (SVR) and 20 patients without SVR were selected for a JAK/STAT signaling genes transcript analysis using multiplex reverse transcription-polymerase chain reaction. Transcripts that were upregulated or downregulated were further validated in 100 patients. Results: Suppressor of cytokine signaling 1 (SOCS1) expression was upregulated in SVR patients compared with non-SVR patients (relative quantification = 2.14) based on a multiplex reverse transcription-polymerase chain reaction analysis. We further analyzed SOCS1 expression in 100 patients. We found that SOCS1 expression did not differ significantly between SVR and non-SVR patients. Conclusion: Peripheral blood SOCS1 expression before treatment was not associated with SVR in HCV genotype 1 patients treated with pegylated IFN-α and ribavirin.

Diabetes and Liver Disease

Article

Nov 2010

The prevalence of type 2 diabetes, in the United States, has increased in association with the increase in the mean weight of Americans indicative of the epidemic of obesity in this country. Complications of type 2 diabetes can be expected to rise in the near future. These complications include vascular, renal, ophthalmologic, and importantly liver disease. Hepatic complications include nonalcoholic fatty liver disease (NAFLD), cirrhosis, hepatocellular carcinoma (HCC), acute liver failure, and post-liver transplantation diabetes. There is, additionally, a relationship between type 2 diabetes and chronic hepatitis C infection with type 2 diabetes being considered an extrahepatic manifestation of chronic hepatitis C infection. The association of diabetes and liver disease is being increasingly recognized. The morbidity and mortality of acute and chronic liver disease in patients with diabetes, particularly type 2 diabetes, will continue to rise in Americans in the immediate and near future.

Prediction of the response of chronic hepatitis C to interferon alfa: A statistical analysis of pretreatment variables

Article

Full-text available

Dec 1993

Pretreatment variables that could predict the response of chronic hepatitis C to interferon alfa treatment have not been fully assessed. Eighteen baseline variables were evaluated in a series of 100 consecutive patients treated with a 12 month course of interferon alfa. For the purposes of this study, response was defined as the return to normal of aminotransferase activities before the third month of treatment. Seventy per cent of the patients responded to treatment. Six variables were associated with an increased likelihood of response assessed by univariate analysis. With stepwise multiple regression analysis assessment, however, only three variables remained independently predictive of response: low gamma glutamyltransferase (gamma GT) activities (p < 0.001), absence of obesity (p = 0.005), and absence of cirrhosis (p = 0.01). The response rate in patients with gamma GT activities < 0.66 mu kat/l (n = 55) was 78% and 60% in patients with values > 0.66 mu kat/l (n = 45) (p = 0.048). Response was attained in 75% of non-obese patients (n = 80), compared with only 50% of obese patients (n = 20) (p = 0.03). Finally, 80% of patients without cirrhosis (n = 76) responded, while among those with cirrhosis (n = 24) the response rate was only 37% (p < 0.001). All 23 patients without cirrhosis, <40 years old, and with gamma GT activities <0.66 mu kat/l responded to treatment, while only 28.5% of 14 patients with cirrhosis, >40 years old, and with gamma GT activities >0.66 mu kat/l responded to interferon alfa (p<0.001). Those findings may be useful when evaluating interferon alfa trials and it is suggested that this treatment should be applied early in the course of chronic hepatitis C.

The Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 but Not SOCS2 Proteins Inhibit Interferon-mediated Antiviral and Antiproliferative Activities

Article

Full-text available

Jan 1999

The suppressor of cytokine signaling (SOCS) proteins are a family of cytokine-inducible negative regulators of cytokine signaling. Interferon (IFN)-γ treatment induces the expression of SOCS1, SOCS2, and SOCS3 mRNAs. To examine the effect of SOCS proteins on IFN-mediated Janus-activated kinase/signal transducers and activators of transcription (STAT) signaling, HeLa- and MCF-7-derived stable cell lines expressing SOCS1, SOCS2, and SOCS3 proteins were established. SOCS1 and SOCS3 but not SOCS2 inhibited the tyrosine phosphorylation and nuclear translocation of STAT1 in response to IFN stimulation. The IFN-mediated antiviral and antiproliferative activities were consistently blocked by the constitutive expression of SOCS1 and SOCS3 but not SOCS2 proteins. The maximum inhibitory activities of SOCS1 and SOCS3 proteins toward the activation of STAT1 were observed at very low levels of SOCS protein expression. In addition, SOCS1 exhibited a much stronger inhibitory activity toward the activation of STAT1 than did SOCS3. These results suggest that SOCS1 and SOCS3 but not SOCS2 are inhibitors of IFN-mediated Janus-activated kinase/STAT signaling pathways.

PEG IFN alfa-2a in patients with chronic hepatitis C

Article

Full-text available

Dec 2000

Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-?? in the Adipose Tissue of Obese Mice

Article

Full-text available

Jan 2002

SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF-alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance.

Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection

Article

Full-text available

Sep 2002
NEW ENGL J MED

Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin. In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes

Article

Full-text available

May 2003

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.

Obesity and its nurturing effect on hepatitis C

Article

Full-text available

Oct 2003

Arthur J Mccullough

Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms

Article

Full-text available

Jul 2004

Insulin resistance is a pathophysiological component of type 2 diabetes and obesity and also occurs in states of stress, infection, and inflammation associated with an upregulation of cytokines. Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed. Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling.

Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse

Article

Full-text available

Aug 2004

Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.

Activation of Tumor Necrosis Factor-?? System in Chronic Hepatitis C Virus Infection

Article

Dec 1997

Tumor necrosis factor-a (TNF-a)plays a central role in the host's immunomodulatoryresponse to infective agents. To evaluate theTNF-a system in patients with chronic hepatitis Cvirus (HCV) infection, plasma, serum, and peripheral bloodmononuclear cells (PBMC) were prospectively collectedfrom 53 patients and 33 healthy control subjects.Circulating TNF-a and TNF receptors were assayed by their respective enzyme immunoassays. Inaddition, TNF-a mRNA was quantitated in PBMC usinga branched DNA assay, and production of TNF-a byPBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infectionhad a higher level of circulating TNF-a comparedto healthy control subjects (9.62 ± 6.01 vs 3.66± 1.23 pg/ml, P 6 cells/ml)between patients with chronic HCV infection (14.2± 36.5 pg/ml, N = 11) and healthy subjects (11.9± 14.0 pg/ml, N = 14, P = NS). However, patientswith chronic HCV infection produced more TNF-a upon stimulation withlipopolysaccharide compared to healthy control subjects(1278 ± 693 pg/ml, N = 11, vs 629 ± 689pg/ml, N = 14, P < 0.05). These data indicate thatthe TNF-a system is activated in patients with chronicHCV infection.

Relationship between the expression of interferon-alpha receptor mRNA and the histological progress of hepatitis C virus associated chronic liver diseases

Article

Aug 1996
J GASTROEN HEPATOL

Histological progress is one of the predictors of an unfavourable response to interferon (IFN) therapy in hepatitis C virus (HCV)-associated chronic liver diseases (CLD). The aim of the present study was to investigate whether histological progress has an association with the expression of IFN receptor (IFN-Rc) in the liver. Expression of mRNA of the IFN-Rc for IFN-α was investigated by reverse transcription polymerase chain reaction using liver biopsy specimens from 37 HCV-associated CLD comprising 11 liver cirrhosis (LC) and 26 chronic hepatitis (CH) cases. IFN-α and IFN-β mRNA were detected in over 90% of subjects. In contrast, the detection rate of IFN-Rc mRNA in chronic persistant hepatitis, chronic hepatitis 2A, chronic hepatitis 2B and liver cirrhosis (LC) was 100, 71.4, 22.2 and 0%, respectively. The absence of IFN-Rc mRNA was significantly associated with the severity of fibrosis of the liver. These results indicated that IFN-Rc expression decreases with the histological progress of the disease, suggesting that lower expression of IFN-Rc mRNA may be partially responsible for the poor IFN response in LC.

Formulation and Application of a Numerical Scoring System for Assessing Histological Activity in Asymptomatic Chronic Active Hepatitis

Article

Sep 1981
HEPATOLOGY

A Histology Activity Index has been developed which generates a numerical score for liver biopsy specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. Under code, three pathologists and three hepatologists evaluated 14 liver biopsy specimens obtained from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between severity of liver biopsy lesions as judged by conventional histological descriptions and Histology Activity Index scores. Significant differences in Histology Activity Index score occurred in only 2 of 28 duplicate scorings of biopsy specimens by two observers. This system provides definitive endpoints for statistical analysis of serial changes in liver histology and offers an alternative to the use of conventional pathological descriptions in following the natural history and treatment responses of asymptomatic chronic active hepatitis.

Clinical and histologic predictors of response to interferon-α in patients with chronic hepatitis C viral infection

Article

Dec 1994

To evaluate if any pretreatment characteristics of patients with chronic hepatitis C (HCV) can be used to predict response to the current recommended dose (3 million units three times a week) and higher doses of interferon- (IFN), we retrospectively assessed the response of 37 patients with HCV who were treated with IFN. Sixteen patients (43%) responded to the standard dose of IFN with normalization of ALT. Weight and liver histology were found to be significant factors for response. The responders weighed significantly less than nonresponders (161.8 35.5 lb versus 200.3 45.4 lb,P=0.008). Seventy-five percent of patients with chronic lobular or persistent hepatitis were responders, whereas only 28% of patients with more advanced hepatitis responded (P=0.01). There was no correlation between the degree of bile duct damage or steatosis and response rate. This study suggests that obesity and severe histologic injury are negative predictive factors of response to the current recommended dose of IFN. The adequacy of the current recommended dose of IFN in overweight patients needs to be investigated.

Classification of Chronic Viral Hepatitis: a need for reassessment

Article

Dec 1991
J HEPATOL

Peter J. Scheuer

Identification of a Sequence in the PEPCK Gene That Mediates a Negative Effect of Insulin on Transcription

Article

Sep 1990

Phosphoenolpyruvate carboxykinase (PEPCK) governs the rate-limiting step in gluconeogenesis. Glucocorticoids and adenosine 3',5'-monophosphate (cAMP) increase PEPCK gene transcription and gluconeogenesis, whereas insulin has the opposite effect. Insulin is dominant, since it prevents cAMP and glucocorticoid-stimulated transcription. Glucocorticoid and cAMP response elements have been located in the PEPCK gene and now a 15-base pair insulin-responsive sequence (IRS) is described. Evidence for a binding activity that recognizes this sequence is presented.

Homeostatis model assessment - Insulin Resistance and Beta-Cell Function From Fasting Plasma-Glucose and insulin concentration in man

Article

Aug 1985

The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

A detailed analysis of the Knodell score and other histologic parameters as predictors of response to interferon therapy in chronic Hepatitis C

Article

May 1995

Unlabelled: The Knodell score is inaccurate at predicting response to interferon alpha (IFN-alpha) therapy in patients with hepatitis C. Our aim was to see if specific histologic parameters, including iron deposition in liver biopsies, are better predictors of response to IFN-alpha than the total Knodell score. Thirty-five unselected patients were studied who had hepatitis C treated with IFN-alpha between 1990 and 1993, and pretreatment serum iron indices and liver needle biopsies performed. Biopsies were divided for light microscopy and quantitative iron determination. H&E-stained slides were graded for components I, II, III, IV, and total Knodell score. Quantitative determinations were percentage of portal triads with inflammation, piecemeal necrosis, lymphoid aggregates, and inflamed bile ducts; percentage of lobules with inflammation or acidophilic bodies; and percentage of triads with positive iron stain. Complete responders (CR) to IFN-alpha were defined by normalization of serum alanine aminotransferase (< or = 40 IU/liter), and noncomplete responders (NCR) by partial or no response. Data were analyzed statistically. CR had < 40% of triads positive for iron (P = 0.02) and lower serum ferritin (P = 0.05) and higher scores for lobular necrosis (P = 0.04). The percentage of iron-positive triads correlated only with cirrhosis. Addition of cirrhosis to percentage of iron-positive triads did not improve the predictive power of the portal iron. CR and NCR did not differ with respect to total Knodell score or any of the other individual parameters except Knodell II. Conclusions: (a) Individual features of lobular necrosis and iron staining in portal triads are better predictors of response to IFN-alpha than the total Knodell score.(ABSTRACT TRUNCATED AT 250 WORDS)

Pretreatment serum HCV RNA levels and HCV genotype are the main and independent prognostic factors of sustained response to interferon therapy in chronic hepatitis C

Article

Oct 1995

The aim of the study was to determine the respective influence of pretreatment serum hepatitis C virus (HCV) RNA levels and HCV genotype on the response to interferon (IFN) alfa in patients with chronic hepatitis C. We retrospectively studied 141 patients with chronic hepatitis C included in two consecutive controlled trials of IFN alfa. A sustained response was observed in 28, a response followed by relapse in 43, and no response in 70 patients. Pretreatment serum HCV RNA quantitation with the branched DNA (bDNA) assay and HCV genotyping with reverse hybridization assay (LiPA) were performed in all patients. Seventy-four percent of the patients had detectable serum HCV RNA (43%, 77% and 84%) in the three groups of patients with sustained response, relapse, and no response, respectively (P = .005). Mean serum HCV RNA level were 1.4 +/- 6 x 10(6), 4.8 +/- 6 x 10(6), and 3.9 +/- 5 x 10(6) genomes/mL in patients with sustained response, response and relapse, and no response, respectively (P < .01). Genotype 1b was found in 7%, 47%, and 46% of the patients in the three response groups, respectively. By univariate analysis, age, source, and duration of HCV infection, serum HCV RNA levels, and HCV genotypes were significantly different in the three response groups. By multivariate analysis, the only independent factors associated with sustained response were low serum HCV RNA levels and HCV genotype other than 1b. Pretreatment serum HCV RNA levels and HCV genotype are the main and independent factors associated with sustained response to IFN therapy.

Tumor Necrosis Factor : A Key Component of the Obesity-Diabetes Link

Article

Dec 1994
DIABETES

Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.

Tumor necrosis factor ?? gene expression and the response to IFN in chronic hepatitis C

Article

Feb 1996

Tumor necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic properties that is induced in a variety of pathological situations including viral infections. In this work, we analyzed the expression of TNF-alpha gene in patients with chronic hepatitis C. Serum TNF-alpha levels were found to be elevated in all chronic hepatitis C patients including those cases presenting sustained biochemical remission of the disease after interferon therapy. Untreated patients with chronic hepatitis C showed increased TNF-alpha messenger RNA (mRNA) levels in the liver and mononuclear cells as compared with healthy controls. After completion of treatment with interferon, patients experiencing sustained complete response showed values of TNF-alpha mRNA, both in the liver and in peripheral mononuclear cells, within the normal range, significantly lower than patients who did not respond to interferon and than those with complete response who relapsed after interferon withdrawal. Pretreatment values of TNF-alpha mRNA were lower in long-term responders to interferon than in cases who failed to respond to the treatment. Values of TNF-alpha mRNA in the liver or in mononuclear cells were higher in specimens with positive hepatitis C virus (HCV) RNA than in those samples where the virus was undetectable. Neither the intensity of the liver damage nor the amount of HCV RNA in serum or in cells showed correlation with the levels of TNF-alpha transcripts in peripheral mononuclear cells but it was found that high TNF-alpha values were associated with genotype 1b. In conclusion, there is an enhanced expression of TNF-alpha in HCV infection. High levels of this cytokine may play a role in the resistance to interferon therapy.

Relationship between the intrahepatic expression of interferon-?? receptor mRNA and the histological progress of hepatitis C virus-associated chronic liver diseases

Article

Sep 1996

Histological progress is one of the predictors of an unfavourable response to interferon (IFN) therapy in hepatitis C virus (HCV)-associated chronic liver diseases (CLD). The aim of the present study was to investigate whether histological progress has an association with the expression of IFN receptor (IFN-Rc) in the liver. Expression of mRNA of the IFN-Rc for IFN-alpha was investigated by reverse transcription polymerase chain reaction using liver biopsy specimens from 37 HCV-associated CLD comprising 11 liver cirrhosis (LC) and 26 chronic hepatitis (CH) cases. IFN-alpha and IFN-beta mRNA were detected in over 90% of subjects. In contrast, the detection rate of IFN-Rc mRNA in chronic persistent hepatitis, chronic hepatitis 2A, chronic hepatitis 2B and liver cirrhosis (LC) was 100, 71.4, 22.2 and 0%, respectively. The absence of IFN-Rc mRNA was significantly associated with the severity of fibrosis of the liver. These results indicated that IFN-Rc expression decreases with the histological progress of the disease, suggesting that lower expression of IFN-Rc mRNA may be partially responsible for the poor IFN response in LC.

Effect of obesity on pharmacokinetics and biologic effect of interferon-?? in hepatitis C

Article

Feb 1997

To examine potential adverse effects of obesity in reducing the response to interferon-alpha (IFN-alpha) in chronic hepatitis C (HCV), IFN-alpha and HCV RNA levels in serum and the 2',5'-oligoadenylate synthetase (2-5 OAS) levels in peripheral blood mononuclear cells (PBMC) were compared between six obese and five nonobese patients before and after a single, 10 mIU dose of IFN-alpha2b. There were no differences in the mean histologic activity index between the two groups. The maximal IFN concentration and the area under the serum IFN concentration-time curve were higher in nonobese patients. These two parameters were inversely correlated with body weight and body surface area. No differences were found in the mean reduction in HCV RNA levels between the two groups following IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5 OAS level (2-5 OAS response ratio) was greater in the nonobese patients, suggesting stronger biologic response upon exposure to exogenous IFN-alpha in nonobese patients.

STATs and gene regulation

Article

Oct 1997

J. E. Jr Darnell

STATs (signal transducers and activators of transcription) are a family of latent cytoplasmic proteins that are activated to participate in gene control when cells encounter various extracellular polypeptides. Biochemical and molecular genetic explorations have defined a single tyrosine phosphorylation site and, in a dimeric partner molecule, an Src homology 2 (SH2) phosphotyrosine-binding domain, a DNA interaction domain, and a number of protein-protein interaction domains (with receptors, other transcription factors, the transcription machinery, and perhaps a tyrosine phosphatase). Mouse genetics experiments have defined crucial roles for each known mammalian STAT. The discovery of a STAT inDrosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins.

Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection

Article

Dec 1997

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the host's immunomodulatory response to infective agents. To evaluate the TNF-alpha system in patients with chronic hepatitis C virus (HCV) infection, plasma, serum, and peripheral blood mononuclear cells (PBMC) were prospectively collected from 53 patients and 33 healthy control subjects. Circulating TNF-alpha and TNF receptors were assayed by their respective enzyme immunoassays. In addition, TNF-alpha mRNA was quantitated in PBMC using a branched DNA assay, and production of TNF-alpha by PBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infection had a higher level of circulating TNF-alpha compared to healthy control subjects (9.62 +/- 6.01 vs 3.66 +/- 1.23 pg/ml, P < 0.001). They also had higher circulating levels of TNF receptors compared to control (CD120a: 3323 +/- 1267, pg/ml, N = 49 vs 1855 +/- 422 pg/ml, N = 33, P < 0.001; CD120b: 1290 +/- 650 pg/ml, N = 51, vs 863 +/- 207 pg/ml, N = 33, P < 0.001). Plasma TNF-alpha level correlated with circulating CD120a (r = 0.52, N = 49, P < 0.001) and weakly with CD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-alpha also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and alpha-GST (r = 0.31, N = 43, P = 0.042), but not with serum HCV RNA levels. There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS). There was also no difference in the spontaneous production of TNF-alpha by PBMC (1 x 10[6] cells/ml) between patients with chronic HCV infection (14.2 +/- 36.5 pg/ml, N = 11) and healthy subjects (11.9 +/- 14.0 pg/ml, N = 14, P = NS). However, patients with chronic HCV infection produced more TNF-alpha upon stimulation with lipopolysaccharide compared to healthy control subjects (1278 +/- 693 pg/ml, N = 11, vs 629 +/- 689 pg/ml, N = 14, P < 0.05). These data indicate that the TNF-alpha system is activated in patients with chronic HCV infection.

TNF-alpha and insulin resistance: summary and future prospects

Article

Jun 1998

While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling.

Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C

Article

Jun 1998

To evaluate the usefulness of easily assessable morphological parameters in liver biopsies in order to predict efficacy of interferon-alpha (IFN) treatment in patients with chronic hepatitis C. Inflammatory activity and fibrosis (according to Scheuer), and the hepatic iron content (according to Rowe and DiBisceglie) were assessed in pre-treatment liver biopsies of 73 de novo patients with chronic hepatitis C. Furthermore the presence of fat, lymphoid aggregates, and bile duct lesions was evaluated. With respect to IFN therapy patients were classified as responders alanine aminotransferase (ALT) normal and negative hepatitis C virus (HCV) RNA in serum at the end of treatment, n = 33) or non-responders (n = 40). Non-responders had more advanced fibrosis (P = 0.0001) and more extensive iron storage (P = 0.0008) than responders. In contrast absence of stainable iron was frequently (46%) associated with sustained response. Absence of fat droplets in hepatocytes was associated with response (P = 0.0001). Stepwise logistic regression analysis indicated that the stage of fibrosis, the hepatic iron grade, and the presence or absence of fat were independent predictors of response. Liver biopsy provides useful information for selection of patients with hepatitis C for IFN therapy.

Association of diabetes mellitus and chronic hepatitis C virus infection

Article

Feb 1999

While patients with liver disease are known to have a higher prevalence of glucose intolerance, preliminary studies suggest that hepatitis C virus (HCV) infection may be an additional risk factor for the development of diabetes mellitus. To further study the correlation of HCV infection and diabetes, we performed a retrospective analysis of 1,117 patients with chronic viral hepatitis and analyzed whether age, sex, race, hepatitis B virus (HBV) infection, HCV infection, and cirrhosis were independently associated with diabetes. In addition, a case-control study was conducted to determine the seroprevalence of HCV infection in a cohort of 594 diabetics and 377 clinic patients assessed for thyroid disease. In the former study after the exclusion of patients with conditions predisposing to hyperglycemia, diabetes was observed in 21% of HCV-infected patients compared with 12% of HBV-infected subjects (P =.0004). Multivariate analysis revealed that HCV infection (P =.02) and age (P =.01) were independent predictors of diabetes. In the diabetes cohort, 4.2% of patients were found to be infected with HCV compared with 1.6% of control patients (P =.02). HCV genotype 2a was observed in 29% of HCV-RNA-positive diabetic patients versus 3% of local HCV-infected controls (P <.005). In conclusion, the data suggest a relatively strong association between HCV infection and diabetes, because diabetics have an increased frequency of HCV infection, particularly with genotype 2a. Furthermore, it is possible that HCV infection may serve as an additional risk factor for the development of diabetes, beyond that attributable to chronic liver disease alone.

Expression of interferon receptor genes in the liver as a predictor of interferon response in patients with chronic hepatitis C

Article

Aug 1999

Interferon (IFN) receptor mRNA expression patterns in the liver have been shown to correlate with the effectiveness of IFN therapy in patients with hepatitis C virus (HCV) infection. However, it is not clear to what extent this factor contributes to the short (primary)- and long (sustained)-term results of IFN treatment with respect to biochemical and virological remission. Eighty-two patients who subsequently received lymphoblastoid IFN-alpha therapy underwent liver biopsies before IFN therapy. Possible factors that might correlate with IFN response were chosen and analyzed. The primary biochemical and virological responses at the end to treatment (24 weeks) were 63% and 43% vs. 46% and 32% for sustained biochemical and virological remission at the end of follow-up (48 weeks), respectively. In univariate analysis, the absence of HCV genotype 1b, a low titer of HCV RNA, and the expression of IFN receptor mRNA were significantly correlated with sustained biochemical and virological responses to IFN therapy. Multiple logistic regression analysis showed that IFN receptor mRNA expression and the absence of genotype 1b were significant predictors of the sustained biochemical and virological effectiveness of IFN therapy. IFN receptor mRNA expression predicted a sustained virological response to IFN therapy with a positive predictive value of 100% with genotype non-1b and had a negative predictive value of 97% with genotype 1b. It is concluded that expression of IFN receptor genes in the liver is a useful index for predicting the short- and long-term efficacy of IFN therapy in patients with chronic HCV infection.

IFN-alpha Receptor mRNA Expression in a United States Sample with Predominantly Genotype 1a/I Chronic Hepatitis C Liver Biopsies Correlates with Response to IFN Therapy

Article

Oct 1999
J INTERF CYTOK RES

Our aim was to assess whether, in the United States, with the predominant hepatitis C viral (HCV) genotypes 1a/I and 1b/II, hepatic interferon-alpha receptor (IFNAR) mRNA expression correlated with response to IFN therapy, levels of HCV RNA, or histologic activity index (HAI). Nine of 24 patients (38%) had an initial response to IFN treatment, 5 of whom (21%) had a sustained response. The corrected hepatic IFNAR mRNA expression (measured by RT-PCR) for the sustained responder group (mean +/- SE, 0.16 +/- 0.06, n = 5) was significantly higher than for the nonresponding group (0.059 +/- 0.01, n = 15) (p < 0.02). Patients who relapsed had an intermediate value (0.092 +/- 0.029, n = 4). Higher IFNAR expression was inversely correlated with a lower serum HCV RNA titer (p < 0.01), and responders to IFN treatment tended to have a lower titer of HCV RNA (p = 0.056). We found no significant correlation between the amounts of IFNAR with (1) the total HAI (low HAI < or = 7, IFNAR 0.076 +/- 0.013, n = 10; high HAI > or = 8, IFNAR 0.092 +/- 0.027, n = 14, ns) or (2) individual inflammation, necrosis, or fibrosis components of the HAI. As with Japanese HCV patients with genotypes 1b/II-2b/IV, higher hepatic IFNAR mRNA expression in the United States with predominant genotypes 1a/I and 1b/II appears to correlate with response to IFN therapy and a low HCV RNA titer but not with the total HAI or its components.

Increased Risk of Type 2 Diabetes in Noncirrhotic Patients With Chronic Hepatitis C Virus Infection

Article

May 2000

To investigate whether patients with chronic hepatitis C virus (HCV) infection without evidence of cirrhosis have an increased risk of diabetes mellitus (DM) and to evaluate possible risk factors for diabetes in this group. We conducted a case-control study of 45 consecutive eligible patients with HCV infection and no clinical, scintigraphic, or histological evidence of cirrhosis, and a control group of 90 subjects without liver disease matched by age, sex, and body mass index and similar in their origin distribution. Eighty-eight patients with chronic hepatitis B virus (HBV) infection with no evidence of cirrhosis were also evaluated. The diagnosis of diabetes was based on the 1997 American Diabetes Association criteria. Fifteen patients (33%) with HCV infection were found to have type 2 diabetes compared with 5.6% in the control group without liver disease (P < .001) and 12% in the group with HBV infection (P = .004). Comparison of the patients with and without diabetes revealed that positive family history of diabetes, HCV 1b genotype, and a more severe liver histology were significantly associated with DM. Patients with chronic HCV infection have an increased prevalence of type 2 diabetes, and this prevalence is independent of cirrhosis. The pathogenesis is intriguing, appears to be unique to HCV, and requires further study.

SOCS: Physiological suppressors of cytokine signaling

Article

Sep 2000

Cytokines regulate cellular behavior by interacting with receptors on the plasma membrane of target cells and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling. The SOCS family consists of eight proteins: SOCS1-SOCS7 and CIS, each of which contains a central Src-homology 2 (SH2) domain and a C-terminal SOCS box. The expression of CIS, SOCS1, SOCS2 and SOCS3 is induced in response to stimulation by a wide variety of cytokines, and overexpression of these proteins in cell lines results in inhibition of cytokine signaling. Thus, SOCS proteins appear to form part of a classical negative feedback loop. The analysis of mice lacking SOCS1 has revealed that it is critical in the negative regulation of IFN(gamma) signaling and in the differentiation of T cells. Additionally, the analysis of mouse embryos lacking SOCS3 suggests that SOCS3 negatively regulates fetal liver erythropoiesis, probably through its ability to modulate erythropoietin (Epo) signaling. Thus, the use of gene targeting has confirmed that SOCS proteins regulate cytokine signaling in a physiological setting.

Regulation of expression of the rat SOCS-3 gene in hepatocytes by growth hormone, interleukin-6 and glucocorticoids: mRNA analysis and promoter characterization

Article

Nov 2000

Suppressors of cytokine signalling (SOCS) represent a newly discovered family of molecules that seem to play an important role in the shutting off of cytokine and possibly peptide hormone action. Thus, understanding the mechanisms controlling their expression is of cardinal importance. In the present study, we have cloned the rat SOCS-3 gene and analyzed its expression and the functioning of its promoter in hepatocytes. Expression of SOCS-3 mRNA, which is very weak in freshly isolated cells, tended to increase when hepatocytes were incubated without hormones. Growth hormone (GH) and, to a much larger extent, interleukin-6 (IL-6) rapidly activated mRNA synthesis whereas glucocorticoids (GC) strongly inhibited both basal and hormone-dependent expressions. A short promoter fragment (-137/+35) responded maximally to GH and IL-6 (a threefold stimulation for each effector) and to GC (a 70-80% inhibition), whereas longer promoter sequences supported higher basal activity and lower positive hormonal responses. Deletion and mutation analyses indicated that all hormonal responses were dependent on two cis-acting sequences termed the G-rich and the A/T-rich elements. Only the A/T-rich element was active in a heterologous context, thus behaving as a typical enhancer. Unexpectedly, the two signal transducer and activator of transcription (STAT) binding sites found immediately upstream of the G-rich motif didn't seem to participate in either GH or IL-6 effect, despite the fact that one of them strongly responded to IL-6 when placed in front of a heterologous promoter. Finally, the negative regulation of SOCS-3 promoter by GC that may contribute to gene silencing in vivo, appeared to involve interactions of the GC receptor with other transcription factors and not direct binding to DNA, as no GC-response element was found in the sequence.

IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3

Article

Oct 2000

Interleukin-10 (IL-10) has been used in the treatment of viral hepatitis in interferon-alpha (IFN-alpha) non-responders while patients who have high levels of IL-10 are poorly responsive to IFN-alpha. The mechanism underlying such controversial functions of IL-10 remains unknown. Here we demonstrated that injection of IL-10 into mice attenuated IFN-alpha-induced signal transducer and activator transcription factor (STAT)1 tyrosine phosphorylation in the liver. Reverse transcriptase-polymerase chain reaction assay demonstrated that mouse liver expressed high levels of IL-10 receptor 2 (IL-10R2) but low levels of IL-10R1. Injection of IL-10 into mice activated STAT3 but not STAT1 tyrosine phosphorylation and induced suppressor of cytokine signal 2 (SOCS2), SOCS3, and cytokine-inducible SH2 protein (CIS) mRNA expression in the liver. Furthermore, overexpression of SOCS2 or SOCS3 inhibited IFN-alpha-induced reporter activity in hepatic cells. These findings suggest that IL-10 inhibits IFN-alpha-activated STAT1 in the liver, at least in part, by inducing SOCS2, SOCS3, and CIS expression, which may be responsible for the resistance of IFN-alpha therapy in patients who have high levels of IL-10 and recommends that IL-10 treatment for viral hepatitis should be cautious.

Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic HCV

Article

Jun 2001
CLIN BIOCHEM

(i) To characterize serum cytokine levels of tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL 6), IL 8 and IL 12 in non-cirrhotic patients with chronic hepatitis C, (ii) to correlate the levels of these cytokines with the degree of the disease at the basal level, (iii) to correlate these levels with the response to therapy, (iv) to compare profiles of cytokines in monotherapy (MT) versus combination therapy (CT), and (v) to compare the immunomodulatory effects of MT versus CT. 47 patients were enrolled in the study. The controls were 120 volunteers (recruited from students and staff) that did not present HCV RNA positive and were not known to suffer any other metabolic disease. Thirty patients formed the other group of controls, with alcoholic liver disease (ALD). Serum cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA). The sustained responders (SRs) have basal values much lower than relapsed responders (RRs) and non-responders (NRs) regardless of the therapy. Cytokines can be used as non-invasive markers for sustained response and as monitors for the outcome of therapy.

Tumor necrosis factor a attenuates interferon-a signaling in the liver: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy

Article

Aug 2001

Although interferon α (IFN-α ) has been used for a decade to treat viral hepatitis, a disease that affects millions of people worldwide, more than 60% of viral hepatitis patients respond poorly. It has been reported that high levels of tumor necrosis factor α (TNF-α ) correlated highly with resistance to IFN-α therapy. Here we demonstrate that injection of TNF- α suppresses IFN-α signaling and markedly induces expression of suppressor of cytokine signaling 3 (SOCS3) and SH2 containing protein-tyrosine phosphatase 2 (SHP2) in the liver. TNF- α induction of SOCS3 and SHP2 remains unchanged while induction of STAT1 protein expression is completely abolished in IL-6-deficient mice. Immunoprecipitation experiments show that injection of TNF- α increases SHP2 association with JAKs. Overexpression of SOCS3 and SHP2 inhibits IFN-α signaling in hepatic cells. Injection of carbon tetrachloride, which is known to induce TNF- α in the liver, attenuates IFN- α signaling in the liver. This attenuation is also observed in TNF- α receptor II- (TNF-R2-) deficient mice but is markedly diminished in TNF-R1-deficient mice. Taken together, these findings suggest that TNF- α may be involved in resistance to IFN- α therapy by induction of SOCS3 and SHP2, and they could be therapeutic targets for improving the efficacy of IFN-α therapy.

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial

Article

Oct 2001

A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

Intrahepatic mRNA levels of interferon γ and tumor necrosis factor α and response to antiviral treatment of chronic hepatitis C

Article

Jul 2001
J Hum Virol

The impact of intrahepatic messenger RNA (mRNA) levels of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) on the outcome of antiviral treatment of chronic hepatitis C was evaluated. Semiquantitative mRNA determination was performed on 36 pretreatment liver biopsies by reverse transcription/competitive polymerase chain reaction. Sustained response (normal aminotransferase levels and negative hepatitis C virus [HCV] RNA for more than 6 months) was achieved in 13 patients, whereas 23 of 36 patients did not achieve sustained response (12 partial responders, 11 complete nonresponders). In sustained responders, pretreatment intrahepatic mRNA levels of IFN-gamma and TNF-alpha were lower than in nonsustained responders (IFN-gamma, 0.23 +/- 0.10 vs. 0.35 +/- 0.07, respectively; p = 0.024 and TNF-alpha, 1.2 +/- 0.7 vs. 2.3 +/- 1.4, respectively; p= 0.009); similarly, HCV viral load was lower in sustained responders than in nonresponders (663,424 +/- 756,389 copies/mL vs. 1,656,713 +/- 1,517,683 copies/mL, respectively; p = 0.037). In addition, TNF-alpha mRNA levels were correlated to HCV viral load and liver fibrosis scores. Higher intrahepatic mRNA levels of IFN-gamma and TNF-alpha may reflect interferon resistance of HCV strains and may contribute to tissue damage in patients refractory to antiviral treatment.

Effect of Combined Interferon-α Induction Therapy and Ribavirin on Chronic Hepatitis C Virus Infection: a Randomized Multicentre Study

Article

Mar 2002

The efficacy of interferon-alpha (IFN) induction in combination with ribavirin for chronic hepatitis C virus (HCV) infection is not known. A total of 256 treatment-naive HCV RNA-positive patients with biopsy-confirmed chronic hepatitis were enrolled in a randomized multicentre study. The patients received either standard combination therapy with 3 MIU interferon-alpha2b thrice weekly for 26 weeks or 6 MIU interferon-alpha2b daily for 4 weeks and 3 MIU 3/7 days for 22 weeks. All patients received ribavirin 1000 mg or 1200 mg (weight dependent) daily during the 26-week treatment period. Patients were monitored for HCV RNA during and following treatment. The sustained virological response rates (26 weeks after end of treatment) were 54% and 47% for patients receiving IFN induction/ribavirin and standard IFN/ribavirin, respectively (P = 0.35). Among patients infected with genotype 1a/1b, the sustained response rates were 32% and 35%. In patients infected with genotype 2b/3a IFN induction/ribavirin led to a sustained response rate of 80% as compared to 65% in the standard combination therapy group (P = 0.073). Steatosis was more frequently seen in liver biopsies from patients infected with genotype 3a as compared to genotypes la/lb. Among genotype 1a/1b infected patients. steatosis was a highly significant predictor of failure to achieve sustained virological response. Logistic regression analysis (multivariate analysis) showed that independent predictors of sustained virological response were low age, female gender, genotype 2b/3a and HCV RNA negativity at 2 weeks. IFN induction in combination with ribavirin does not increase the sustained virological response rate among patients infected with HCV. Absence of steatosis is an independent predictor of sustained virological response in patients infected with genotypes 1a/1b.

Interferon-?? activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes

Article

Apr 2002
GASTROENTEROLOGY

Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-alpha signal pathway in primary human hepatocytes. The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses. Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) 1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-alpha up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through down-regulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation. IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver.

Optimal therapy of hepatitis C

Article

Dec 2002

The highest response rates to antiviral therapy for the treatment of chronic hepatitis C have been achieved using the combination of peginterferon and ribavirin. Recently completed controlled trials have reported rates of sustained virological response (SVR) between 50% and 60% in patients treated with higher doses of peginterferon and ribavirin, which was 5% to 10% higher with standard doses of interferon alfa and ribavirin. The major determinant of outcome of therapy is hepatitis C virus (HCV) genotype. With the combination of peginterferon and ribavirin, patients with genotype 1 achieve response rates of 40% to 45%, compared with rates approaching 80% with genotypes 2 or 3. Importantly, patients with HCV genotype 1 achieve higher rates of response with 48 weeks than with 24 weeks of therapy, whereas patients with genotypes 2 and 3 are adequately treated with a 24-week course. Furthermore, patients with genotypes 2 and 3 require only 800 mg of ribavirin daily to achieve optimal response rates, whereas 1,000 to 1,200 mg daily is needed for patients with genotype 1. Future studies should focus on optimizing the dose of peginterferon and ribavirin by patient characteristics, particularly on resolving the issue of weight-based dosing. For patients with good prognostic factors, a lower dose and shorter course of peginterferon may be adequate for full effect. Importantly, research is needed to show how treatment regimens can best be applied to other patient groups with hepatitis C, such as patients with acute hepatitis, human immunodeficiency virus coinfection, renal disease, solid-organ transplant, neuropyschiatric disease, autoimmunity, and alcohol or substance abuse.

Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: Therapy efficacy as consequence of tripartite interaction of viral, host and interferon treatment-related factors

Article

Dec 2002
J HEPATOL

The mechanism of variable response to interferon (IFN) monotherapy in patients infected with HCV genotype 2a is still unclear. Here we investigated the response in a large group of patients infected with genotype 2a. We evaluated 394 consecutive non-cirrhotic naive patients infected with genotype 2a who received IFN monotherapy for 24 weeks, including initial aggressive induction therapy. Of these, 97 were also evaluated for early viral kinetics in serum and treatment efficacy. The overall sustained response (SR) rate was 68.3% (viral load <1.0 Meq/ml (82.4%); >/=1.0 (52.4%)). Multivariate analysis identified five independent factors associated with SR; viral load <1.0 Meq/ml, total IFN dose > or =700 million units, hepatocyte steatosis none or mild, albumin > or =3.9 g/dl, and alanine aminotransferase > or =75 IU/l. The kinetic study showed that serum viral clearance at < or =1 week was the best predictor of SR, and persistence at > or = 4 weeks was a predictor of non-SR. Our study suggests that viral, host and IFN treatment-related factors determine the response to IFN monotherapy in patients infected with HCV genotype 2a. Further, we report that IFN monotherapy is very effective for patients with genotype 2a, especially for those with low viral load; and that early viral kinetics is useful as a predictor of the response.

IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3

Article

Apr 2003
FASEB J

Eighty percent of patients newly infected with the hepatitis C virus (HCV) develop chronic infection, suggesting that HCV can develop effective strategies to escape the unspecific and specific immune response of the host. Because SOCS molecules have been recognized to be powerful inhibitors of cytokine signaling via the Jak/STAT pathway, virus-induced expression of these molecules should be an efficient instrument to counteract the cellular response toward interferons (IFNs), an essential part of first line antiviral immune response. This study shows that overexpression of HCV core protein inhibits IFN-alpha-induced tyrosine phosphorylation and activation of STAT1 in hepatic cells. With the use of a STAT1-YFP fusion protein, further evidence is given that HCV core is capable to inhibit nuclear translocation of STAT1. Inhibition of STAT1-tyrosine phosphorylation was accompanied by the induction of SOCS3-mRNA expression, suggesting that the HCV core protein impairs IFN-alpha-induced signal transduction via induction of SOCS3 expression. HCV core protein was competent to partially rescue growth of a genetically engineered influenza A virus lacking its own IFN antagonist. These IFN-antagonistic properties of the HCV core protein may be part of the molecular basis of IFN-alpha unresponsiveness in about one-half of chronically infected HCV-patients.

Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C

Article

Aug 2003

It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. We assess the effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis. We analyzed 1,428 naïve patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001). The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007). In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001). Steatosis was associated with HCV genotype 3, triglycerides, high body mass index, age, fibrosis stage, and lower virologic response to treatment. In conclusion, sustained disappearance of the virus is associated with reduction of steatosis in genotype 3 as well as a correction of baseline low serum cholesterol.

High Body Mass Index Is an Independent Risk Factor for Nonresponse to Antiviral Treatment in Chronic Hepatitis C

Article

Sep 2003

The aim of this study was to determine if body mass index (BMI) was an independent predictor of response to antiviral treatment in patients with chronic hepatitis C. A retrospective review was performed of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000. A sustained response was defined as either negative hepatitis C virus (HCV) RNA by polymerase chain reaction and/or normal alanine aminotransferase (ALT) level (only in those treated before availability of HCV RNA testing) 6 months following completion of therapy. All patients were classified into one of 3 groups according to BMI (normal, <25 kg/m(2); overweight, 25-30 kg/m(2); obese, >30 kg/m(2)). A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin. Patients were excluded if predetermined clinical characteristics were unavailable. Using logistic regression, and after adjusting for the examined variables (age, sex, history of alcohol consumption >50 g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood ratio tests showed significant differences in response to treatment according to BMI group (P =.01), genotype (P <.01), and cirrhosis (P <.01). Those with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 compared with those with genotype 1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients. Hepatic steatosis was not an independent risk factor for response to antiviral treatment. In conclusion, obesity, only when defined as a BMI greater than 30 kg/m(2), is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment.

Barthel, A. & Schmoll, D. Novel concepts in insulin regulation of hepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab. 285, E685-E692

Article

Nov 2003

The regulation of hepatic gluconeogenesis is an important process in the adjustment of the blood glucose level, and pathological changes in the glucose production of the liver are a central characteristic in type 2 diabetes. The pharmacological intervention in signaling events that regulate the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and the catalytic subunit glucose-6-phosphatase (G-6-Pase) is regarded as a potential strategy for the treatment of metabolic aberrations associated with this disease. However, such intervention requires a detailed understanding of the molecular mechanisms involved in the regulation of this process. Glucagon and glucocorticoids are known to increase hepatic gluconeogenesis by inducing the expression of PEPCK and G-6-Pase. The coactivator protein PGC-1 has been identified as an important mediator of this regulation. In contrast, insulin is known to suppress both PEPCK and G-6-Pase gene expression by the activation of PI 3-kinase. However, PI 3-kinase-independent pathways can also lead to the inhibition of gluconeogenic enzymes. This review focuses on signaling mechanisms and nuclear events that transduce the regulation of gluconeogenic enzymes.

Host factors and failure of IFN-?? treatment in HCV

Article

Apr 2004

Failure of interferon-alpha (IFN-alpha) treatment in patients with chronic hepatitis C virus (HCV) infection is a challenging obstacle for clinical and experimental hepatology. Both viral and host factors have been implicated in reducing responsiveness to IFN-alpha therapy. The role of viral factors has been studied extensively and has been summarized in several review articles; however, much less attention has been paid to host factors. In this paper, we review evidence of host factor involvement in IFN-alpha treatment failure. We discuss possible underlying mechanisms responsible for these effects. Potential therapeutic strategies to enhance the effectiveness of IFN-alpha therapy for HCV are also proposed.

Steatosis and Liver Cell Apoptosis in Chronic Hepatitis C: A Mechanism for Increased Liver Injury

Article

May 2004

Steatosis is increasingly recognized as a cofactor influencing the progression of fibrosis in chronic hepatitis C; however, the mechanisms by which it contributes to liver injury remain uncertain. We studied 125 patients with chronic hepatitis C to assess the effect of steatosis on liver cell apoptosis and the expression of Bcl-2, Bcl-x(L), Bax, and tumor necrosis factor alpha (TNF-alpha) and the relationship between liver cell apoptosis and disease severity. A significant increase in liver cell apoptosis was seen in liver sections with increasing grade of steatosis (r = 0.42; P <.0001). Hepatic steatosis and previous heavy alcohol consumption were the only two variables independently associated with the apoptotic index. Increasing steatosis was associated with decreased Bcl-2 mRNA levels and an increase in the proapoptotic Bax/Bcl-2 ratio (r = -0.32, P =.007; and r = 0.27, P =.02, respectively). In the absence of steatosis, increased liver cell apoptosis was not associated with stellate cell activation or fibrosis (r = 0.26, P =.11; r = 0.06, P =.71, respectively). In contrast, in the presence of steatosis, increasing apoptosis was associated with activation of stellate cells and increased stage of fibrosis (r = 0.35, P =.047; r = 0.33, P =.03, respectively), supporting the premise that the steatotic liver is more vulnerable to liver injury. In patients with hepatitis C virus genotype 3, there was a significant correlation between TNF-alpha mRNA levels and active caspase-3 (r = 0.54, P =.007). In conclusion, these observations suggest a mechanism whereby steatosis contributes to the progression of liver injury in chronic hepatitis C. Further investigation will be required to determine the molecular pathways responsible for the proapoptotic effect of steatosis and whether this increase in apoptosis contributes directly to fibrogenesis.

SOCS-1 and SOCS-3 inhibit IFN-alpha-induced expression of the antiviral proteins 2,5-OAS and MxA

Article

Aug 2004

Although the use of IFN-alpha in combination with ribavirin has improved the treatment efficacy of chronic hepatitis C virus (HCV) infection, 20-50% of patients still fail to eradicate the virus depending on the HCV genotype. Recently, overexpression of HCV core protein has been shown to inhibit IFN signaling and induce SOCS-3 expression. Aim of this study was to examine the putative role of SOCS proteins in IFN resistance. By Western blot analysis, a 4-fold induction of STAT-1/3 phosphorylation by IFN-alpha was observed in mock-transfected HepG2 clones. In contrast, IFN-induced STAT-1/3 phosphorylation was considerably downregulated by SOCS-1/3 overexpression. In mock-transfected cells, IFN-alpha induced 2',5'-OAS and myxovirus resistance A (MxA) promoter activity 40- to 80-fold and 10- to 35-fold, respectively, and this effect was abrogated in SOCS-1/3 overexpressing cells. As detected by Northern blot technique, IFN-alpha potently induced 2',5'-OAS and MxA mRNA expression in the control clones. Overexpression of SOCS-1 completely abolished both 2',5'-OAS and MxA mRNA expression, whereas SOCS-3 mainly inhibited 2',5'-OAS mRNA expression. Our results demonstrate that SOCS-1 and SOCS-3 proteins inhibit IFN-alpha-induced activation of the Jak-STAT pathway and expression of the antiviral proteins 2',5'-OAS and MxA. These data suggest a potential role of SOCS proteins in IFN resistance during antiviral treatment.

Insulin resistance is associated with chronic hepatitis C and fibrosis progression

Article

Dec 2003
GASTROENTEROLOGY

Chronic hepatitis C virus infection is associated with an increased prevalence of type 2 diabetes. We hypothesized that virus-induced insulin resistance may be a mechanism for fibrogenesis in chronic hepatitis C virus infection. In 260 hepatitis C virus-infected subjects, we examined the relationship between histological findings and anthropometric and biochemical data, including insulin resistance determined by the homeostasis model assessment (HOMA-IR). We also compared fasting serum insulin, C peptide, and HOMA-IR levels between the subset of 121 hepatitis C virus patients with stage 0 or 1 hepatic fibrosis and 137 healthy volunteers matched by sex, body mass index, and waist-hip ratio. Hepatitis C virus-infected subjects with stage 0 or 1 hepatic fibrosis had higher levels of insulin, C peptide, and HOMA-IR (all P < or = 0.01) compared with matched healthy controls. In the 250 hepatitis C virus patients (fibrosis stage 0 to 4), viral genotype and portal, but not lobular, inflammation were univariate predictors of HOMA-IR. By multiple linear regression analysis, independent predictors of HOMA-IR included body mass index (P < 0.001), previous failed antiviral treatment (P < 0.001), portal inflammatory grade (P < 0.001), and genotype 3 status (P = 0.01). Genotype 3 had significantly lower HOMA-IR than other genotypes (which were comparable when adjusted for effects of the remaining independent predictors). HOMA-IR was an independent predictor for the degree of fibrosis (P < 0.001) and the rate of fibrosis progression (P = 0.03). Hepatitis C virus may induce insulin resistance irrespective of the severity of liver disease, and this effect seems to be genotype specific. Further, our findings support the hypothesis that insulin resistance may contribute to fibrotic progression in chronic hepatitis C virus infection.

What is disrupting IFN-α's antiviral activity?

Article

Sep 2004
TRENDS BIOTECHNOL

Despite advances in treatment strategies for hepatitis C virus (HCV), a significant proportion of patients fail to achieve viral clearance following treatment with pegylated interferon (IFN)-alpha plus ribavirin. Many of these individuals show elevated levels of tumor necrosis factor (TNF)-alpha compared with normal controls, and recent data have implicated this cytokine in the negative regulation of IFN-alpha. Although a therapeutic opportunity for TNF-alpha antagonists might exist for reducing inflammation in chronic HCV disease, further exploration is required to identify the key mediators of responsiveness to IFN-alpha. In particular, the interplay should be clarified between host response factors [e.g. IFN-alpha, IFN-gamma, suppressor of cytokine signaling (SOCS), TNF-alpha and others] and pathogen-associated molecular patterns [PAMPs, e.g. lipopolysaccharide (LPS) and CpG DNA] in HCV disease; this information might guide future therapies aimed at improving IFN-alpha responsiveness.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

Abstract

No full-text available

Recommended publications

Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C:...

Role of hepatic HCV-RNA level on the severity of chronic hepatitis C and response to antiviral thera...

Viral and host factors of liver steatosis associated with chronic C hepatitis and effect of steatosi...

Liver Protein Profiling in Chronic Hepatitis C: Identification of Potential Predictive Markers for I...