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

Amir Shlomai, Maya Mouler Rechtman, Ela Olga Burdelova, Alona Zilberberg, Sarit Hoffman, Irit Solar, Sigal Fishman, Zamir Halpern, Ella H. Sklan

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish
Pages (from-to)867-873
Number of pages7
JournalJournal of Hepatology
Volume57
Issue number4
DOIs
StatePublished - Oct 2012

Keywords

  • Diabetes
  • Hepatitis C virus
  • Insulin resistance
  • Oxidative stress
  • Peroxisome proliferator-activated receptor gamma co-activator 1α

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