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

✍ Scribed by Valerio Pazienza; Sophie Clément; Paolo Pugnale; Stéphanie Conzelman; Michelangelo Foti; Alessandra Mangia; Francesco Negro

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 602 KB
• Volume: 45
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21634

✦ Synopsis

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.