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-β£), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-β£ 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;47:2127-2133.)
H epatitis C virus (HCV) and nonalcoholic fatty liver disease (NAFLD) are the two most common causes of chronic liver disease in North America. HCV affects approximately 2%, NAFLD 6 to 14%, and nonalcoholic steatohepatitis (NASH) 3% to 5% of the general population in the United States. The concomitant presence of obesity, NAFLD, and HCV has significant consequences on the liver histology. 1 The interaction of these various factors in HCV patients predisposes them to steatosis, thus increasing the risk of fibrosis and liver cancer. 2,3 Recently HCV infection is noted to be an independent predictor of diabetes mellitus, and the latter as a predictor of treatment failure in patients with hepatitis C. 4 HCV induces several complex mechanisms that lead to inflammation, insulin resistance, steatosis, fibrosis, apoptosis, altered gene expression, and hepatocellular carcinoma (HCC). 2,3,5,6 Increased oxidative stress is now proposed as a major initiator of HCV selected pathogenesis. 7 With emerging insight into the pathogenic mechanism leading to insulin resistance, HCV is now viewed to cause a metabolic syndrome, as opposed to simple viral infection. Significant attention is presently being drawn toward the HCV molecular pathways that lead to insulin resistance. By treating HCV as a metabolic disease, novel approaches toward understanding the pathogenesis of