The metabolic regulator PGC-1α links hepatitis C virus infection to hepatic insulin resistance

Background & Aims: Chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and diabetes mellitus. Peroxisome proliferator-activated receptor-gamma co-activator 1a (PGC-1a) is a transcriptional co-activator involved in the initiation of gluconeogenesis in the liver. Increased hepatic expression of PGC-1a has been implicated in insulin resistance. We investigated whether modulation of PGC-1a levels following HCV infection underlies HCV-associated hepatic insulin resistance. Methods: HCV genomes were expressed in hepatoma cells followed by analysis of PGC-1a and gluconeogenesis levels. Results: PGC-1a was robustly induced in HCV infected cells. PGC-1a induction was accompanied by an elevated expression of the gluconeogenic gene glucose-6 phosphatase (G6Pase) and increased glucose production. The induction of gluconeogenesis is HCV dependent, since interferon treatment abolishes PGC-1a and G6Pase elevation and decreases glucose output. Moreover, PGC-1a knockdown resulted in a significant reduction of G6Pase levels in HCV full length replicon cells, emphasizing the central role of PGC-1a in the exaggerated gluconeogenic response observed in HCV patients. Treatment of HCV replicon cells with the antioxidant N-acetylcysteine resulted in reduction of PGC1a levels, suggesting that HCV-induced oxidative stress promoted PGC-1a upregulation. Finally, both PGC-1a and G6Pase RNA levels were significantly elevated in liver samples of HCV infected patients, highlighting the clinical relevance of these results. Conclusions: PGC-1a is robustly induced following HCV infection, resulting in an upregulated gluconeogenic response, thereby linking HCV infection to hepatic insulin resistance. Our results suggest that PGC-1a is a potential molecular target for the treatment of HCV-associated insulin resistance. 2012 European Association for the Study of the Liver. Published