The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

Hepatology. 2007 May;45(5):1164-71. doi: 10.1002/hep.21634.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Down-Regulation
  • Hepacivirus / genetics
  • Humans
  • Insulin Receptor Substrate Proteins
  • Liver Neoplasms
  • Nuclear Proteins / physiology
  • PPAR gamma / physiology
  • Phosphoproteins / biosynthesis*
  • Proteasome Endopeptidase Complex / metabolism
  • Serine / metabolism
  • Suppressor of Cytokine Signaling Proteins / physiology
  • Transfection
  • Viral Core Proteins / genetics
  • Viral Core Proteins / physiology*

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Nuclear Proteins
  • PPAR gamma
  • Phosphoproteins
  • SOCS7 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Viral Core Proteins
  • Serine
  • Proteasome Endopeptidase Complex