The metabolic regulator PGC-1α links hepatitis C virus infection to hepatic insulin resistance.
OBJECTIVE
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.
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.
Amir
A
Shlomai
Maya Mouler
MM
Rechtman
Ela Olga
EO
Burdelova
Alona
A
Zilberberg
Sarit
S
Hoffman
Irit
I
Solar
Sigal
S
Fishman
Zamir
Z
Halpern
Ella H
EH
Sklan
D000111:Acetylcysteine / Q000494:pharmacology; D045744:Cell Line, Tumor; D018274:Electroporation; D055785:Gene Knockdown Techniques; D005838:Genotype; D005943:Gluconeogenesis / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012093:Replicon; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D014779:Virus Replication
D006360:Heat-Shock Proteins; D016898:Interferon-alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D012367:RNA, Viral; D014157:Transcription Factors; D005952:Glucose-6-Phosphatase; D000111:Acetylcysteine