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Metabolic basis of NAFLD pathogenesis. Insulin resistance associated with metabolic syndrome leads to unbalance between gain (red arrows) and loss (green arrows) of fat in liver. Insulin resistance in adipocyte tissue leads to massive mobilization of fatty acids (FFAs) from fat-overloaded adipocytes into liver, due to the suppression of the inhibitory effect of insulin on hormone-sensitive lipase (HLS), the rate-limiting enzyme catalyzing adipocyte TG lipolysis. Peripheral insulin resistance also leads to an overload of glucose (not internalized by peripheral tissues) and insulin (due to compensatory hyperinsulinaemia). Delayed insulin resistance in liver as compared with other tissues allows for the exacerbated insulin- and glucose-induced hepatic effects, with overproduction of hepatic FFAs via activation of the transcription factors sterol regulatory binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP), respectively. FFAs are stored as TGs in lipid droplets, exported as very low density lipoprotein (VLDL), and oxidized by mitochondrial β-oxidation, as compensatory mechanisms to the increased FFA uptake and synthesis. Lipophagy helps to degrade TGs from lipid droplets and to deliver FFAs for these exportation routes. However, VLDL production and lipophagy are impaired in NAFLD, and enhanced mitochondrial FFA β-oxidation leads to oxidative stress due to exacerbated leakage of electrons from the electron transport chain. Oxidative stress is aggravated by the concomitant FFA-mediated induction of CYP2E1, a cytochrome that performs futile cycles with release of electrons into the cytosol
Source publication
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems t...
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NAFLD is the world's most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharma...
In the last decade, non-alcoholic fatty liver disease (NAFLD) and particularly its evolution to nonalcoholic steatohepatitis (NASH) have become a leading cause of chronic liver disease and cirrhosis as well as an important risk factor for hepatocellular carcinoma. Oxidative stress is a common feature of NAFLD/NASH and plays a key role in the comple...
Irene Perez,1 Fabian J Bolte,1 William Bigelow,1 Zachary Dickson,2 Neeral L Shah2 1Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA; 2Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USACorrespondence: Neeral L ShahDivision of Gastroenterology and Hepatology, University of Vi...
Several studies have shown that liver fibrosis, and even cirrhosis can be reversed, disproving the old “dogma” that cirrhosis is irreversible. In addition to scaring, vascular alterations appear to be critically important in the progression of chronic liver diseases. To overcome the “tipping-point” of cirrhosis, we need to understand in depth what...
Citations
... Obesity is also closely related to NAFLD, with approximately 80% of obese individuals affected by NAFLD [13,14]. An increase in visceral fat and inflammation plays a significant role in NAFLD development, with those with the highest amount of visceral fat and the largest adipocyte diameter at the highest risk of developing NAFLD among obese individuals [15][16][17][18][19][20]. ...
Background
The aim of this study was to examine the association between different metabolic obesity phenotypes and the non-alcoholic fatty liver disease (NAFLD).
Methods
This cross-sectional analysis utilized data from the baseline phase of the Ravansar non-communicable diseases (RaNCD) cohort study, which involved 8,360 adults. Participants with a Fatty Liver Index (FLI) score of ≥ 60 was classified as having NAFLD. The FLI score was calculated using liver non-invasive markers and anthropometric measurements. Participants were categorized into four phenotypes based on the presence or absence of metabolic syndrome and obesity. Logistic regression analysis was used to evaluate the association of NAFLD and obesity phenotypes.
Results
According to the FLI index, the prevalence of NAFLD was 39.56%. Participants with FLI scores of ≥ 60 had higher energy intake compared to those in the FLI < 60 group (P = 0.033). In subjects with metabolically unhealthy phenotypes, the level of physical activity was lower compared to those with metabolically healthy phenotypes. The risk of NAFLD in males with the metabolically healthy-obese phenotype increased by 8.92 times (95% CI: 2.20, 15.30), those with the metabolically unhealthy-non-obese phenotype increased by 7.23 times (95% CI: 5.82, 8.99), and those with the metabolically unhealthy-obese phenotype increased by 32.97 times (95% CI: 15.70, 69.22) compared to the metabolically healthy-non-obese phenotype. Similarly, these results were observed in females.
Conclusion
This study demonstrated that the risk of NAFLD is higher in individuals with metabolically healthy/obese, metabolically unhealthy/non-obese, and metabolically unhealthy/obese phenotypes compared to those with non-obese/metabolically healthy phenotypes.
... The metabolic breakdown of PAHs generates reactive oxygen species (ROS) and triggers an inflammatory response, disrupting the body's oxidation-antioxidation balance. This oxidative stress damages DNA and proteins, ultimately causing complications such as insulin resistance and impaired lipid metabolism (Akhavan Rezayat et al. 2018;Bessone et al. 2018;Efriza et al. 2023;Regnault et al. 2014). Liver toxicity is a common outcome, mediated by disruptions in blood lipids and inflammation. ...
Objective
To investigate the effect of urinary PAHs on MAFLD.
Methods
The study included 3,136 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2016. Among them, 1,056 participants were diagnosed with MAFLD and were designated as the case group. The analysis of the relationship between monohydroxy metabolites of seven PAHs in urine and MAFLD was carried out using logistic regression and Bayesian kernel regression (BKMR) models.
Results
In single-pollutant models, the concentration of 2-hydroxynaphthalene (2-OHNAP) was positively correlated with MAFLD (OR = 1.47, 95% CI 1.18, 1.84), whereas 3-hydroxyfluorene (3-OHFLU) and 1-hydroxypyrene (1-OHPYR) demonstrated a negative correlation with MAFLD (OR = 0.59, 95% CI 0.48 0.73; OR = 0.70, 95% CI 0.55, 0.89). Conversely, in multi-pollutant models, 2-OHNAP, 2-hydroxyfluorene (2-OHFLU), 2-hydroxyphenanthrene, and 3-hydroxyphenanthrene (2&3-OHPHE) displayed positive correlations with MAFLD (OR = 6.17, 95% CI 3.15, 12.07; OR = 2.59, 95% CI 1.37, 4.89). However, 3-OHFLU and 1-OHPYR continued to exhibit negative correlations with MAFLD (OR = 0.09, 95% CI 0.05, 0.15; OR = 0.62, 95% CI 0.43, 0.88). Notably, the BKMR analysis mixtures approach did not indicate a significant joint effect of multiple PAHs on MAFLD, but identified interactions between 3-OHFLU and 2-OHFLU, 1-OHPYR and 2-OHFLU, and 1-OHPYR and 3-OHFLU.
Conclusion
No significant association was found between mixed PAHs exposure and the risk of MAFLD. However, interactions were observed between 3-OHFLU and 2-OHFLU. Both 2-OHFLU and 2&3-OHPHE exposure are significant risk factors for MAFLD, whereas 3-OHFLU is a key protective factor for the disease.
... Subsequently, GSEA was applied to analyze the biological behavior of the two clusters. The GSEA enrichment analysis showed that the electron transport chain oxphos system in mitochondria, oxidative stress induced senescence, metabolic disorders of biological oxidation enzymes, triglyceride metabolism, diseases of programmed cell death and proinflammatory and profibrotic mediators were upregulated in cluster 1 ( Figure 5H), all of which have been shown to be associated with the pathogenesis of NAFLD (39,40). In conclusion, these results strongly indicated that the key DE-DRGs might be involved in the development and progression of NAFLD and were related to immune modulation. ...
... Furthermore, we identified 312 NAFLD-specific DEGs in DEGs and WGCNA, of which 293 were up-regulated and 19 were down-regulated. Functional enrichment analysis in the present study found that the NAFLD-specific DEGs were associated with important pathogenesis processes and pathways of NAFLD (39,40), including Non−alcoholic fatty liver disease pathway, Oxidative phosphorylation pathway, and PPAR signaling pathways. These findings strongly indicated that the NAFLD-specific DEGs identified in this study play an important role in the occurrence and development of NAFLD and should be further investigated. ...
Backgrounds
Non-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD.
Methods
Gene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples.
Results
Through the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity.
Conclusion
This comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease’s development.
... MASLD is characterized by the presence of hepatic steatosis along with at least one cardiometabolic risk factor, such as elevated body mass index, disrupted glucose metabolism, high blood pressure, high triglyceride, and low high-density cholesterol (HDL-C) levels. The development and progression of MASLD involves multiple risk factors, including age, sex, ethnicity, hormonal status, genetic predisposition, epigenetic factors, and dietary habits [7][8][9][10][11] . Patients with MASLD generally have a hypercaloric and unhealthy diet characterized by high consumption of fat esterified with saturated and polyunsaturated free fatty acids (FFAs), cholesterol, fructose, and low antioxidant vitamins [12] . ...
... Patients with MASLD generally have a hypercaloric and unhealthy diet characterized by high consumption of fat esterified with saturated and polyunsaturated free fatty acids (FFAs), cholesterol, fructose, and low antioxidant vitamins [12] . MASLD is defined as an increase in liver fat content with a threshold of more than 5% and regularly coexists with metabolic disorders such as insulin resistance, type 2 diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease [7,8] . When hepatic steatosis is observed on liver histology without a history of alcohol consumption,it can be classified as metabolic dysfunction-associated steatotic liver (MASL) [7,8] . ...
... MASLD is defined as an increase in liver fat content with a threshold of more than 5% and regularly coexists with metabolic disorders such as insulin resistance, type 2 diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease [7,8] . When hepatic steatosis is observed on liver histology without a history of alcohol consumption,it can be classified as metabolic dysfunction-associated steatotic liver (MASL) [7,8] . However, when there is steatosis, hepatocyte ballooning and lobular inflammation, with or without perisinusoidal fibrosis, it is sub-categorized as metabolic dysfunction-associated steatohepatitis (MASH) [13] . ...
Aim: Hepatocellular carcinoma (HCC) in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) is expected to be a significant public health issue in the near future. Therefore, understanding the tumor microenvironment interactions in MASLD-induced HCC is crucial, and the development of relevant preclinical models is needed. Hence, we aimed to determine the effects of a MASLD-mimicking microenvironment (ME) on the aggressiveness of HCC cells and identify target genes that drive HCC by developing a 3D-in vitro co-culture system.
Methods: A 3D co-culture system mimicking the MASLD-ME was created with LX-2 liver stellate cells embedded in 3D collagen gel in the lower and SNU-449 HCC cells on the upper parts of Boyden chambers, and cells were grown in an optimized metabolic medium (MM). The effects of NAFLD-ME on motility, sphere formation, proliferation, and cell cycle of SNU-449 cells were tested by Boyden chamber, 3D sphere formation, XTT, and Flow cytometry, respectively. The protein expression/activation profiles of motile SNU-449 cells that passed the membrane toward NAFLD-ME or control condition were investigated using a multiplex protein profiling system DigiWest and confirmed with RT-PCR, WB, and Flow cytometry. IDH2 levels were examined in primary human HCC and adjacent liver tissues by IHC and in TCGA and CPTAC cohorts by bioinformatics tools.
Results: MM treatment increased fat accumulation, motility, and spheroid formation of both SNU-449 and LX-2 cells. MASLD-ME induced activation of LX2 cells, leading to the formation of bigger colonies with many intrusions compared to related controls. DigiWest analysis showed that metabolism-related proteins such as IDH2 were the most affected molecules in SNU-449 cells that migrated toward the MASLD-ME compared to those that migrated toward the control condition. Downregulation of IDH2 expression was confirmed in SNU-449 cells grown in MASLD-ME, in primary HCC tumor samples by IHC, and in HCC patient cohorts by bioinformatics analysis.
Conclusion: This study reports the potential involvement of MASLD-ME in the downregulation of IDH2 expression and promoted motility and colonization capacity of HCC cells. The 3D MASLD model presented in this study may be useful in investigating the mechanistic roles of MASLD-ME in HCC.
... • Homeostasis model assessment of insulin resistance score ≥2.5. • Plasma high-sensitivity C-reactive protein level >2 mg/L [6][7][8]. ...
... The non-MAFLD population referred to patients who do not meet the above conditions. According to alcoholic beverage consumption, MAFLD patients were further classified as MAFLD with alcohol intake and MAFLD without alcohol intake [7]. The aim of the study was to identify prevalence of metabolic associated fatty liver disease (MAFLD) in Fayoum Governorate. ...
... Dysbiosis-induced inflammation can cause the liver to produce reactive oxygen species (ROS), which can harm the liver cells through oxidative stress. This oxidative stress exacerbates liver inflammation further and hastens NAFLD progression [6][7][8]. ...
A prevalent liver condition called non-alcoholic fatty liver disease (NAFLD) may progress into non-alcoholic steatohepatitis (NASH) and cause life-threatening complications like cirrhosis and liver cancer. The development and progression of NAFLD has been linked to the make-up and functioning of the gut microflora. This article reviews the clinical studies reported to investigate the connection between changes in the gut microbiota and metabolic markers in NAFLD patients. According to the study findings, dysbiosis of the gut microflora were observed in NAFLD patients, which are manifested by variations in the proportions of particular bacterial species. These changes are linked to fibrosis, liver inflammation, and metabolic abnormalities. The article also discusses various treatments targeting the gut microbiota, including dietary modifications, exercise, prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation. These therapies are intended to enhance NAFLD outcomes and reestablish the healthy gut microflora. While some studies have shown promising results, further research is needed to establish the optimal approaches, long-term safety, and efficacy of these treatments for NAFLD.
... NAFLD is a complex metabolic dysfunction syndrome with multiple pathologies [4,47], including lipid accumulation and subsequent oxidative stress, inflammation, and DNA damage [48][49][50][51]. Interestingly, the HCF diet promoted nucleotide repair pathways, suggesting the involvement of DNA damage in liver cells ( Figure 4A). ...
... Many different pathologies are involved in the development of NAFLD [4,47]. For instance, lipid accumulation, insulin resistance, inflammation, oxidative stress, and DNA damage can occur [48] [49,50]. Several TCM herbs or formulas for treating NAFLD pathology have been developed. ...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.
... The data suggest that GBA3 promotes the transcription of CPT2, thus alleviating NAFLD by promoting FAO. Our study provides evidence supporting the toxic effects of fatty acid overload on liver cells [35]. Furthermore, it further indicates that the regulation of lipid metabolism is a potential strategy for managing NAFLD. ...
Background:
Excessive lipids accumulation and hepatocytes death are prominent characteristics of non-alcoholic fatty liver disease (NAFLD). Nonetheless, the precise pathophysiological mechanisms are not fully elucidated.
Methods:
HepG2 cells stimulated with palmitic acids and rats fed with high-fat diet were used as models for NAFLD. The impact of Glucosylceramidase Beta 3 (GBA3) on fatty acid oxidation (FAO) was assessed using Seahorse metabolic analyzer. Lipid content was measured both in vitro and in vivo. To evaluate NAFLD progression, histological analysis was performed along with measurements of inflammatory factors and liver enzyme levels. Western blot and immunohistochemistry were employed to examine the activity levels of necroptosis. Flow cytometry and reactive oxygen species (ROS) staining were utilized to assess levels of oxidative stress.
Results:
GBA3 promoted FAO and enhanced the mitochondrial membrane potential without affecting glycolysis. These reduced the lipid accumulation. Rats supplemented with GBA3 exhibited lower levels of inflammatory factors and liver enzymes, resulting in a slower progression of NAFLD. GBA3 overexpression reduced ROS and the ratio of cell apoptosis. Phosphorylation level was reduced in the essential mediator, MLKL, implicated in necroptosis. Mechanistically, as a transcriptional coactivator, GBA3 promoted the expression of Carnitine Palmitoyltransferase 2 (CPT2), which resulted in enhanced FAO.
Conclusions:
Increased FAO resulting from GBA3 reduced oxidative stress and the production of ROS, thereby inhibiting necroptosis and delaying the progression of NAFLD. Our research offers novel insights into the potential therapeutic applications of GBA3 and FAO in the management and treatment of NAFLD.
... In insulin resistance, which represents the key mechanism in MASLD, excess free fatty acids cause an upregulation of mitochondrial citric acid cycle activity, leading to an increased generation of ROS and lipid peroxidation, causing hepatocellular damage [36]. In MASLD, different markers of oxidative stress have been identified in higher levels, as well as antioxidant molecules to counteract the burden of oxidative stress [37]. Oxidative stress is also an established mechanism in the progression from MASLD to MASH [38]. ...
Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress is a well-established cause of organ damage in the liver, the main site of iron storage. Ferroptosis, an iron-dependent mechanism of regulated cell death, has recently been gaining attention in the development of organ damage and the progression of liver disease. We therefore summarize the main mechanisms of iron metabolism, its close connection to oxidative stress and ferroptosis, and its particular relevance to disease mechanisms in metabolic-dysfunction-associated fatty liver disease and potential targets for therapy from a clinical perspective.
... Liver steatosis is the key event defining the course of the disease [5]. Lipid accumulation depends on different metabolic inputs, including insulin resistance, dyslipidemia, and obesity [6][7][8][9]. Under these conditions, the bioavailability of dietary free fatty acids (FFAs) is increased through adipose tissue lipolysis or synthesis via hepatic de novo lipogenesis [7,9,10]. ...
... Lipid accumulation depends on different metabolic inputs, including insulin resistance, dyslipidemia, and obesity [6][7][8][9]. Under these conditions, the bioavailability of dietary free fatty acids (FFAs) is increased through adipose tissue lipolysis or synthesis via hepatic de novo lipogenesis [7,9,10]. Hepatocytes and every other hepatic cell, including hepatic stellate cells (HSCs), are exposed to the steatogenic environment. ...
... In the steatotic liver, hepatocytes assume the majority of the metabolic challenge that excessive lipid levels represent for the liver. However, when its metabolic capacities are exceeded, the accumulation of lipid droplets occurs [7]. Quiescent HSCs are considered a retinoid depot 2 of 14 in a healthy liver, while in chronic liver disease, including MASLD, HSCs are activated mainly by transforming growth factor (TGF)-β, becoming the major source of extracellular matrix proteins leading the fibrogenic response [11]. ...
Different cellular mechanisms influence steatotic liver disease (SLD) progression. The influence of different levels of steatogenic inputs has not been studied in hepatocytes and hepatic stellate cells (HSCs). Methods: HepG2 hepatocytes and LX-2 HSCs were cultured in mild (MS) and severe (SS) steatogenic conditions. TGF-β stimulation was also tested for HSCs in control (T) and steatogenic conditions (MS-T and SS-T). Steatosis was stained with Oil Red, and the proliferation was assayed via WST-8 reduction, apoptosis via flow cytometry, and senescence via SA-β-galactosidase activity. Results: Regarding hepatocytes, steatosis progressively increased; proliferation was lower in MS and SS; and the viability of both conditions significantly decreased at 72 h. Apoptosis increased in MS at 72 h, while it decreased in SS. Senescence increased in MS and diminished in SS. Regarding HSCs, the SS and SS-T groups showed no proliferation, and the viability was reduced in MS at 72 h and in SS and SS-T. The LX-2 cells showed increased apoptosis in SS and SS-T at 24 h, and in MS and MS-T at 72 h. Senescence decreased in MS, SS, and SS-T. Conclusions: Lipid overload induces differential effects depending on the cell type, the steatogenic input level, and the exposure time. Hepatocytes are resilient to mild steatosis but susceptible to high lipotoxicity. HSCs are sensitive to lipid overload, undergoing apoptosis and lowering senescence and proliferation. Collectively, these data may help explain the development of steatosis and fibrosis in SLD.
