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

Valerio Pazienza, Sophie Clément, Paolo Pugnale, Stéphanie Conzelman, Michelangelo Foti, Alessandra Mangia, Francesco Negro

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1164-1171
Number of pages8
JournalHepatology
Volume45
Issue number5
DOIs
Publication statusPublished - May 2007

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Insulin Receptor Substrate Proteins
Down-Regulation
Genotype
Peroxisome Proliferator-Activated Receptors
rosiglitazone
Insulin
Proteins
Cytokines
Sirolimus
Hepatitis C virus nucleocapsid protein
Small Interfering RNA
Insulin Resistance
Molecular Biology
Hepatocellular Carcinoma
Signal Transduction
Cell Line
Infection

ASJC Scopus subject areas

  • Hepatology

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The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. / Pazienza, Valerio; Clément, Sophie; Pugnale, Paolo; Conzelman, Stéphanie; Foti, Michelangelo; Mangia, Alessandra; Negro, Francesco.

In: Hepatology, Vol. 45, No. 5, 05.2007, p. 1164-1171.

Research output: Contribution to journalArticle

Pazienza, Valerio ; Clément, Sophie ; Pugnale, Paolo ; Conzelman, Stéphanie ; Foti, Michelangelo ; Mangia, Alessandra ; Negro, Francesco. / The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. In: Hepatology. 2007 ; Vol. 45, No. 5. pp. 1164-1171.
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