Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance.
Chronic hepatitis C virus (HCV) infection has a significantly increased prevalence of type 2 diabetes mellitus (T2DM). Insulin resistance is a critical component of T2DM pathogenesis. Several mechanisms are likely to be involved in the pathogenesis of HCV-related insulin resistance. Since we and others have previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase, we examined the contribution of these pathways to insulin resistance in hepatocytes. Our experimental findings suggest that HCV core protein alone or in the presence of other viral proteins increases Ser(312) phosphorylation of the insulin receptor substrate-1 (IRS-1). Hepatocytes infected with cell culture-grown HCV genotype 1a or 2a displayed a significant increase in the Ser(473) phosphorylation status of the Ser/Thr kinase protein kinase B (Akt/PKB), while Thr(308) phosphorylation was not significantly altered. HCV core protein-mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK (SP600125) and phosphatidylinositol-3 kinase (LY294002) inhibitors. A functional assay also suggested that hepatocytes expressing HCV core protein alone or infected with cell culture-grown HCV exhibited a suppression of 2-deoxy-d-[(3)H]glucose uptake. Inhibition of the JNK signaling pathway significantly restored glucose uptake despite HCV core expression in hepatocytes. Taken together, our results demonstrated that HCV core protein increases IRS-1 phosphorylation at Ser(312) which may contribute in part to the mechanism of insulin resistance.
Banerjee
Sutapa
S
Division of Infectious Diseases and Immunology, Center for Vaccine Development, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA.
Saito
Kousuke
K
Ait-Goughoulte
Malika
M
Meyer
Keith
K
Ray
Ratna B
RB
Ray
Ranjit
R
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D018936:Hepatitis C Antigens / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014758:Viral Core Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018936:Hepatitis C Antigens; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047428:Protein Kinase Inhibitors; D014758:Viral Core Proteins; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose