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The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype‐specific mechanisms
Author(s) -
Pazienza Valerio,
Clément Sophie,
Pugnale Paolo,
Conzelman Stéphanie,
Foti Michelangelo,
Mangia Alessandra,
Negro Francesco
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21634
Subject(s) - irs1 , insulin receptor , irs2 , biology , downregulation and upregulation , genotype , insulin resistance , signal transduction , insulin receptor substrate , receptor , pi3k/akt/mtor pathway , transfection , endocrinology , insulin , medicine , microbiology and biotechnology , cancer research , cell culture , biochemistry , gene , genetics
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 γ (PPARγ) 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 PPARγ (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. (H EPATOLOGY 2007;45:1164–1171.)