The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms.
Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPARgamma (rosiglitazone) or short interfering RNAs for SOCS-7.


CONCLUSIONS
Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.
Pazienza
Valerio
V
Division of Clinical Pathology, University Hospital, Geneva, Switzerland.
Clément
Sophie
S
Pugnale
Paolo
P
Conzelman
Stéphanie
S
Foti
Michelangelo
M
Mangia
Alessandra
A
Negro
Francesco
F
D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016174:Hepacivirus / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008113:Liver Neoplasms; D009687:Nuclear Proteins / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D014162:Transfection; D014758:Viral Core Proteins / Q000235:genetics / Q000502:physiology*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D010750:Phosphoproteins; C108775:SOCS7 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014758:Viral Core Proteins; D012694:Serine; D046988:Proteasome Endopeptidase Complex