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Heat map presenting differentially expressed proteins. Proteomic profiling was carried out for samples provided by the consortium such as fibroblasts from two patients with steatosis (H0007, H0008) and a non-obese control (H0002).
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Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis. As a result of increases in the prevalences of obesity, insulin resistance, and hyperlipidemia, the number of people with hepatic steatosis continues to increase. Differences in susceptibility to steatohepat...
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Background:
Aberrantly elevated sterol regulatory element binding protein (SREBP), the lipogenic transcription factor, contributes to the development of fatty liver and insulin resistance in animals. Our recent studies have discovered that AMP-activated protein kinase (AMPK) phosphorylates SREBP at Ser-327 and inhibits its activity, represses SREB...
Red cell distribution width (RDW) is a marker of chronic inflammation. Hepatic diseases are often associated with several hematological complications; therefore, high levels of RDW are seen in hepatic diseases. Given the fact that factors which cause non-alcoholic steatohepatitis such as inflammation, oxidative stress, free oxygen
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GPR109A agonists have been used for the treatment of obesity however, the role of GPR109A in regulating aging-associated alterations in lipid metabolism is unknown. In this study we used Gpr109a-/- mice to investigate the effect of aging in the regulation of lipid accumulation. We observed that in mouse and human livers, in addition to Kupffer cell...
We characterized the effect of systemic therapy given after portal vein embolization (PVE) and before hepatectomy on hepatic tumor and functional liver remnant (FLR) volumes. All 76 patients who underwent right PVE from 2002–2016 were retrospectively studied. Etiologies included colorectal cancer (n = 44), hepatocellular carcinoma (n = 17), cholang...
Citations
... Cells of the human foreskin and dermal fibroblast-derived hiPS cell lines A4 and CO2 were generated as described previously [61,62]. The CO2 cells were maintained on Matrigel ® (hESC-qualified; Corning, NY, USA)-coated 6-well plates in mTeSR™ Plus (Stemcell Technologies, Vancouver, BC, Canada). ...
Small extracellular vesicles (sEV) hold enormous potential as biomarkers, drug carriers, and therapeutic agents. However, due to previous limitations in the phenotypic characterization of sEV at the single vesicle level, knowledge of cell type-specific sEV signatures remains sparse. With the introduction of next-generation sEV analysis devices, such as the single-particle interferometric reflectance imaging sensor (SP-IRIS)-based ExoView R100 platform, single sEV analyses are now possible. While the tetraspanins CD9, CD63, and CD81 were generally considered pan-sEV markers, it became clear that sEV of different cell types contain several combinations and amounts of these proteins on their surfaces. To gain better insight into the complexity and heterogeneity of sEV, we used the ExoView R100 platform to analyze the CD9/CD63/CD81 phenotype of sEV released by different cell types at a single sEV level. We demonstrated that these surface markers are sufficient to distinguish cell-type-specific sEV phenotypes. Furthermore, we recognized that tetraspanin composition in some sEV populations does not follow a random pattern. Notably, the tetraspanin distribution of sEV derived from mesenchymal stem cells (MSCs) alters depending on cell culture conditions. Overall, our data provide an overview of the cell-specific characteristics of sEV populations, which will increase the understanding of sEV physiology and improve the development of new sEV-based therapeutic approaches.
... These FPLD2-iPSCs recapitulated the insulin resistance phenotype of the patient with low efficiency of in vitro adipogenic differentiation and less functionality [75] . Recent studies showed the ability to generate adipocytes from hESCs and hiPSCs [76,77] . It has been reported that hiPSC-derived adipocytes, transplanted into mice, are able to sustain their functional characteristics for several weeks [77] , suggesting that these cells can also be used therapeutically to improve metabolic disorders in patients. ...
... Recent studies showed the ability to generate adipocytes from hESCs and hiPSCs [76,77] . It has been reported that hiPSC-derived adipocytes, transplanted into mice, are able to sustain their functional characteristics for several weeks [77] , suggesting that these cells can also be used therapeutically to improve metabolic disorders in patients. Therefore, differentiation of patient-specific hiPSCs into white adipocytes can offer a large number of functional adipocytes for transplantation as a possible way to treat adipocytes-associated disorders as well as studying IR. ...
... These FPLD2-iPSCs recapitulated the insulin resistance phenotype of the patient with low efficiency of in vitro adipogenic differentiation and less functionality [75] . Recent studies showed the ability to generate adipocytes from hESCs and hiPSCs [76,77] . It has been reported that hiPSC-derived adipocytes, transplanted into mice, are able to sustain their functional characteristics for several weeks [77] , suggesting that these cells can also be used therapeutically to improve metabolic disorders in patients. ...
... Recent studies showed the ability to generate adipocytes from hESCs and hiPSCs [76,77] . It has been reported that hiPSC-derived adipocytes, transplanted into mice, are able to sustain their functional characteristics for several weeks [77] , suggesting that these cells can also be used therapeutically to improve metabolic disorders in patients. Therefore, differentiation of patient-specific hiPSCs into white adipocytes can offer a large number of functional adipocytes for transplantation as a possible way to treat adipocytes-associated disorders as well as studying IR. ...
Insulin resistance (IR) is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Several rodent models for both IR and T2D are being used to study the disease pathogenesis; however, these models cannot recapitulate all the aspects of this complex disorder as seen in each individual. Human pluripotent stem cells (hPSCs) can overcome the hurdles faced with the classical mouse models for studying IR. Human induced pluripotent stem cells (hiPSCs) can be generated from the somatic cells of the patients without the need to destroy a human embryo. Therefore, patient-specific hiPSCs can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of genome editing and hiPSCs may provide important information about the genetic factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes. In this review, we summarize the factors involved in the development of IR in the insulin-target tissues leading to diabetes. Also, we highlight the use of hPSCs to understand the mechanisms underlying the development of IR.
... The pathogenesis of NAFLD-NASH is complex, and to date, no approved therapy for NASH exists. HLCs may constitute a valuable tool for pathway testing, disease modelling and development of therapeutic compounds [56][57][58]. Graffmann et al. attempted to develop a novel model system utilizing hESCs and iPSCs of healthy subjects for the development of HLCs. By subsequently inducing lipid overload through administration of oleic acid, the authors modelled the early steatosis stage of NAFLD in HLCs. ...
Dyslipidemias are strongly linked to the development of atherosclerotic cardiovascular disease. Most dyslipidemias find their origin in the liver. In recent years, the differentiation of induced pluripotent stem cells (iPSCs) into hepatocyte-like cells has provided a versatile platform for the functional study of various dyslipidemias, both rare genetic dyslipidemia as well as common lipid disorders associated with insulin resistance or non-alcoholic fatty liver disease. In addition, iPSC-derived hepatocytes can serve as a cell model for developing novel lipid lowering therapies and have the potential of regenerative medicine. This review provides an overview of these developments.
... The iPSCs generated from patients with liver steatosis showed a decrease in the AKT/mTOR signaling molecule and the phenotypes of IR are observed in both liver and skin fibroblasts of the patients. Additionally, it showed that the transcription factor, sterol regulatory element binding transcription factor 1 (SREBF1) and its downstream targets like LIPIN1 (LPIN) and low density lipoprotein receptor are involved in glycerolipid and fatty acid biosynthesis [170]. Recently, we generated the first iPSCs from patients with psoriasis and insulin resistance. ...
In this review, we discuss the insulin resistance (IR) and its development in the insulin target tissues that leads to diabetes. Also, we highlight the use of induced pluripotent stem cells (iPSCs) to understand the mechanisms underlying the development of IR. IR is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Although there are currently several mouse models for both IR and T2D that had provided a lot of information about the disease, these models cannot recapitulate all the aspects of this complex disease as seen in each individual. Patient-specific iPSCs can overcome the hurdles faced with the classical mouse models for studying IR. iPSC technology can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of the genome editing and iPSCs may provide important information about the inherited factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.
... Hepatic steatosis is caused by the abnormal accumulation of predominantly triglycerides in the liver [148] . Histological examinations of liver parenchyma revealed presence of triglyceride droplets in the cytoplasm of hepatocytes and their accumulation in small and large vesicles which impairs liver function and makes this organ more susceptible to other injuries [148] . ...
... Hepatic steatosis is caused by the abnormal accumulation of predominantly triglycerides in the liver [148] . Histological examinations of liver parenchyma revealed presence of triglyceride droplets in the cytoplasm of hepatocytes and their accumulation in small and large vesicles which impairs liver function and makes this organ more susceptible to other injuries [148] . Immunochemical analysis of steatohepatitis performed by Lackner et al [138] showed that in macrovesicular steatosis the IF cytoskeleton was only pushed to the cell periphery by the accumulated triglycerides, as it was also observed in all their cases of steatosis. ...
T. gondii is a globally distributed intracellular protozoan parasite affecting approximately 5-90% of human population and causing a variety of so far neglected diseases and clinical entities in both immunocompromised and immunocompetent individuals. Acute infection of the parasite in mice caused marked reduction in serum butyrylcholinesterase (BChE) activity and liver damage. BChE and acetylcholinesterase (AChE) are biomarkers of low-grade systemic inflammation and earlier it was suggested that the elevation of these two bioparameters may predict development of type 2 diabetes mellitus and Alzheimer's disease. Serum BChE activity was found to be associated with overweight, obesity, and body fat distribution parameters. Recently, a positive association between T. gondii seropositivity and obesity has also been reported. Infection with the parasite was linked with the increase in the number of hepatic stellate cells known to play an important role in the development of fibrosis and its advancement to cirrhosis.of any etiology. Moreover, several authors suggested that hepatitis with a clinical picture resembling acute viral hepatitis result from T. gondii infection. Abnormalities associated with cryptogenic liver cirrhosis markedly affect acquired immunity of the host and probably participate in triggering and persistence of several autoimmune diseases, especially that anti-T. gondii IgG antibodies have been found in the sera of both patients suffering from these clinical entities and in healthy individuals. Oxidative stress and immunosuppresion due to the infection play an important role in these processes. It should be also noted that mammalian as well as the parasite cells, express two cholesteryl ester-synthesizing enzymes, ACAT1 and ACAT2, which share 44-47% of amino acid homology. ACAT1 is present in various cells and tissues, while ACAT2 expression is restricted to hepatocytes and intestinal mucosal cells. The parasite enzymes TgACAT1 and TgACAT2 localized to endoplasmic reticulum can synthesize and store abundant esters of cholesterol and triglycerides. The lifelong persistence and resulting surplus of ACAT1 and ACAT2, and TgACAT1 and TgACAT2 enzymatic activities especially in hepatocytes and/or intestinal cells of the host may therefore at least in part be responsible for development of steatohepatitis, and generation of ballooning hepatocytes, foamy macrophages, and clear cells (foamy) colitis. These abnormalities can be explained by the suppressed autophagy (it regulates lipid metabolism) in the liver due to proliferation of T. gondii. In alcoholic steatohepatitis, ballooning degeneration of hepatocytes may also at least partly result from the fact that ethanol dose-dependently stimulate microneme secretion in T. gondii tachyzoites and parasite attachment to the host cells, thus facilitating infection of the hepatic cells. The increased serum iron levels and hepatic iron overload reported in the patients with nonalcoholic hepatitis may be caused by the excess of NO produced by activated macrophages and hepatic cells of the host, as a defense molecule against infection with the parasite. NO intercepts iron before incorporation into ferritin and directly mobilizes iron from the serum protein in a glutathione-dependent manner. Finally, several reports provided data suggesting that the generation of Mallory-Denk bodies is linked with latent chronic hepatic toxoplasmosis, and HIGHLIGHT TOPIC it was suggested that the elevation of these two bioparameters may predict the development of type 2 diabetes mellitus and Alzheimer's disease [14]. These proposed associations are in line with my previous reports suggesting an important role of T. gondii infection in development of these two clinical entities [15,16]. BChE also serves as a marker predicting the prognosis of diseases [11] because when the serum activity of the enzyme is low, a high-risk of death must be T. gondii cathepsin L and B proteases play an important role in this process. These findings may be supported by the population-based studies demonstrating the link between infection with the parasite and development of liver abnormalities, and the increasing global burden of overweight and obesity in children and adults.
... Hepatic steatosis is caused by the abnormal accumulation of predominantly triglycerides in the liver [148] . Histological examinations of liver parenchyma revealed presence of triglyceride droplets in the cytoplasm of hepatocytes and their accumulation in small and large vesicles which impairs liver function and makes this organ more susceptible to other injuries [148] . ...
... Hepatic steatosis is caused by the abnormal accumulation of predominantly triglycerides in the liver [148] . Histological examinations of liver parenchyma revealed presence of triglyceride droplets in the cytoplasm of hepatocytes and their accumulation in small and large vesicles which impairs liver function and makes this organ more susceptible to other injuries [148] . Immunochemical analysis of steatohepatitis performed by Lackner et al [138] showed that in macrovesicular steatosis the IF cytoskeleton was only pushed to the cell periphery by the accumulated triglycerides, as it was also observed in all their cases of steatosis. ...
... LPL functions as a homodimer, and possesses the functions of both triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake [24]. PPARG regulates fatty acid storage and glucose metabolism, and has been implicated in the pathology of some diseases [25]. ACACA catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis [26]. ...
Trihexanoin is a short-chain triglyceride (SCT). Many studies have reported that SCTs play important roles in the maintenance of intestinal epithelial structure and function. The present work was to investigate the effects of trihexanoin on growth performance, carbohydrate and fat metabolism, as well as intestinal morphology and function in weaned piglets. Twenty weaned piglets (21 ± 2 d) were randomly allocated to one of two treatment groups: The control group (basal diet supplemented with 0.5% soya oil); the TH group (basal diet supplemented with 0.5% trihexanoin). Dietary trihexanoin supplementation significantly reduced diarrhea rate; increased the concentrations of LDL, HDL and total protein in plasma; decreased cholesterol concentrations and glutamyl transpeptidase activity in plasma; improved intestinal morphologic structure; altered the mRNA levels and abundances of proteins related to glycogen and fat metabolism, mucosal barrier function, antioxidant capacity and water transport capacity; and altered the community of intestinal microflora. These results indicate that dietary trihexanoin supplementation could reduce diarrhea, regulate carbohydrate and fat metabolism, exert beneficial effects on the intestinal mucosal barrier, protect the intestinal mucosa from injuries, improve intestinal transport and absorption, and enhance antioxidant capacity. In conclusion, dietary supplementation with 0.5% trihexanoin improves the intestinal function and health of weaned piglets.
... Non-alcoholic fatty liver disease (NAFLD) is diagnosed increasingly worldwide and is considered to be the most common liver disorder in the West (Rector et al., 2008). NAFLD refers to a spectrum of hepatic disorders, ranging from simple hepatic steatosis with no apparent specific symptoms to hepatocellular carcinoma (Jozefczuk et al., 2012). Hepatic steatosis is caused by abnormal accumulation of triglycerides (TG) in the liver due to chemical exposures other than excessive alcohol consumption. ...
Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of disease, ranging from simple fatty liver through steatosis with inflammation and necrosis to cirrhosis. One of the most challenging problems in biomedical research and within the chemical industry is to understand the underlying mechanisms of complex disease, and complex adverse outcome pathways (AOPs). Based on a set of 28 steatotic chemicals with gene expression data measured on primary hepatocytes at three times (2, 8, and 24 h) and three doses (low, medium, and high), we identified genes and pathways, defined as molecular initiating events (MIEs) and key events (KEs) of steatosis using a combination of a time series and pathway analyses. Among the genes deregulated by these compounds, the study highlighted OSBPL9, ALDH7A1, MYADM, SLC51B, PRDX6, GPAT3, TMEM135, DLGDA5, BCO2, APO10LA, TSPAN6, NEURL1B, and DUSP1. Furthermore, pathway analysis indicated deregulation of pathways related to lipid accumulation, such as fat digestion and absorption, linoleic and linolenic acid metabolism, calcium signaling pathway, fatty acid metabolism, peroxisome, retinol metabolism, and steroid metabolic pathways in a time dependent manner. Such transcription profile analysis can help in the understanding of the steatosis evolution over time generated by chemical exposure.
... The pathophysiological complexity of the nonalcoholic fatty liver disease involves inter-organ communications It seems that all four pathophysiological processes involved in the pathogenesis of NAFLD and its sequelae, namely, the accumulation of intrahepatic fat, the inflammation of the liver parenchyma, the fibrosis and the tumorigenesis, may proceed simultaneously, within the same organ. While hastening each other and serving as mutual confounders, these processes develop by deregulation of distinct regulatory networks (13,14). Moreover, all four pathophysiological components of NASH are influenced by the cellular and molecular changes taking place in distant tissues and organs. ...
