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J Hepatol. 2012 Oct;57(4):867-73. doi: 10.1016/j.jhep.2012.06.021. Epub 2012 Jun 23.

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

Author information

1
The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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.

PMID:
22732512
DOI:
10.1016/j.jhep.2012.06.021
[Indexed for MEDLINE]

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