Peroxisome Proliferator-Activated Receptor α L162V Polymorphism in Nonalcoholic Steatohepatitis and Genotype 1 Hepatitis C Virus-Related Liver Steatosis

2005 ◽  
Vol 53 (7) ◽  
pp. 353-359 ◽  
Author(s):  
Hasibe Verdi ◽  
Elif Sare Koytak ◽  
Oğuz Önder ◽  
Ayça Arslan Ergül ◽  
Kubilay Cinar ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Steatosis ◽  
Peroxisome Proliferator ◽  
Genotype 1 ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Peroxisome Proliferator-Activated Receptors and Hepatitis C Virus-Induced Insulin Resistance

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Francesco Negro
Keyword(s):  
Insulin Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Insulin Signalling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Peroxisome Proliferator Activated Receptors ◽  
Chronic Hepatitis C Patients

Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a), insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator-activated receptorγ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.

scholarly journals Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

2015 ◽  
Vol 291 (4) ◽  
pp. 1974-1990 ◽  
Author(s):  
Donna N. Douglas ◽  
Christopher Hao Pu ◽  
Jamie T. Lewis ◽  
Rakesh Bhat ◽  
Anwar Anwar-Mohamed ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Arrest ◽  
Lipid Synthesis ◽  
Reactive Oxygen ◽  
Hcv Infection ◽  
Peroxisome Proliferator ◽  
Oxygen Species ◽  
Peroxisome Proliferator Activated Receptor

Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and β-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor α, which plays a dominant role in the expression of β-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor α is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced β-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced β-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.

scholarly journals Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

2019 ◽  
Vol 295 (4) ◽  
pp. 994-1008 ◽  
Author(s):  
Nancy Magee ◽  
An Zou ◽  
Priyanka Ghosh ◽  
Forkan Ahamed ◽  
Don Delker ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Hepatic Inflammation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep−/−) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep−/− mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep−/− mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep−/− mice. In contrast, livers of ShpHep−/− mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.

Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication

2013 ◽  
Vol 23 (17) ◽  
pp. 4774-4778 ◽  
Author(s):  
Shintaro Ban ◽  
Youki Ueda ◽  
Masao Ohashi ◽  
Kenji Matsuno ◽  
Masanori Ikeda ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Replication ◽  
Peroxisome Proliferator ◽  
Hepatitis C Virus Rna ◽  
Peroxisome Proliferator Activated Receptor ◽  
Virus Rna

Impaired expression of the peroxisome proliferator–activated receptor alpha during hepatitis C virus infection

2005 ◽  
Vol 128 (2) ◽  
pp. 334-342 ◽  
Author(s):  
Sébastien Dharancy ◽  
Mathilde Malapel ◽  
Gabriel Perlemuter ◽  
Tania Roskams ◽  
Yang Cheng ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Peroxisome Proliferator ◽  
Hepatitis C Virus Infection ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha

scholarly journals Transforming Growth Factor β Acts as a Regulatory Molecule for Lipogenic Pathways among Hepatitis C Virus Genotype-Specific Infections

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Tapas Patra ◽  
Reina Sasaki ◽  
Keith Meyer ◽  
Ratna B. Ray ◽  
Ranjit Ray
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Virus Genotype ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hcv Genotype ◽  
Genotype 1A

ABSTRACT Hepatitis C virus (HCV) infection promotes metabolic disorders, and the severity of lipogenic disease depends upon the infecting virus genotype. Here, we have examined HCV genotype 1-, 2-, or 3-specific regulation of lipid metabolism, involving transforming growth factor β (TGF-β)-regulated phospho-Akt (p-Akt) and peroxisome proliferator-activated receptor alpha (PPARα) axes. Since HCV core protein is one of the key players in metabolic regulation, we also examined its contribution in lipid metabolic pathways. The expression of regulatory molecules, TGF-β1/2, phospho-Akt (Ser473), PPARα, sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FASN), hormone-sensitive lipase (HSL), and acyl dehydrogenases was analyzed in virus-infected hepatocytes. Interestingly, HCV genotype 3a exhibited much higher activation of TGF-β and p-Akt, with a concurrent decrease in PPARα expression and fatty acid oxidation. A significant and similar decrease in HSL, unlike in HCV genotype 1a, was observed with both genotypes 2a and 3a. Similar observations were made from ectopic expression of the core genomic region from each genotype. The key role of TGF-β was further verified using specific small interfering RNA (siRNA). Together, our results highlight a significant difference in TGF-β-induced activity for the HCV genotype 2a- or 3a-induced lipogenic pathway, exhibiting higher triglyceride synthesis and a decreased lipolytic mechanism. These results may help in therapeutic modalities for early treatment of HCV genotype-associated lipid metabolic disorders. IMPORTANCE Hepatic steatosis is a frequent complication associated with chronic hepatitis C virus (HCV) infection and is a key prognostic indicator for progression to fibrosis and cirrhosis. Several mechanisms are proposed for the development of steatosis, especially with HCV genotype 3a. Our observations suggest that transforming growth factor β (TGF-β) and peroxisome proliferator-activated receptor alpha (PPARα)-associated mechanistic pathways in hepatocytes infected with HCV genotype 2a and 3a differ from those in cells infected with genotype 1a. The results suggest that a targeted therapeutic approach for enhanced PPARα and lipolysis may reduce HCV genotype-associated lipid metabolic disorder in liver disease.

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