Hepatitis C virus infection: Molecular pathways to metabolic syndrome


  • Muhammad Y. Sheikh,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, University of California San Francisco (UCSF) Fresno Education Program, Community Regional Medical Center, Fresno, CA
    • Associate Professor of Clinical Medicine and Chief, Division of Gastroenterology and Hepatology, UCSF Fresno, Community Regional Medical Center, 2823 Fresno Street, 1st Floor, Endoscopy, Fresno, CA 93721
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    • fax: 559-459-3887

  • Jinah Choi,

    1. School of Natural Sciences, University of California at Merced, Merced, CA
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  • Ishtiaq Qadri,

    1. National Center of Virology and Immunology and National University of Science and Technology, Rawalpindi, Pakistan
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  • Jacob E. Friedman,

    1. Department of Pediatrics, Biochemistry, and Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO
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  • Arun J. Sanyal

    1. Division of Gastroenterology, Virginia Commonwealth University Health System, Richmond, VA
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  • Potential conflict of interest: Nothing to report.


Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen-activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF-α), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-α inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti-inflammatory peroxisome proliferator-activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV-associated IR and provides a direction for future research in the areas of therapeutic intervention. (HEPATOLOGY 2008.)