title: Hepatitis C as a metabolic disease: Implication for the pathogenesis of NASH.
abstract: In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations such as essential mixed cryoglobulinemia, porphyria cutanea tarda or Sjögren's syndrome. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been known, implying hepatitis C as a metabolic disease. In addition, recent epidemiological studies have suggested a linkage between type 2 diabetes and chronic HCV infection. However, the presence of additional factors in patients, such as obesity, aging or cirrhosis, prevents the establishment of a definite relationship between HCV infection and these two conditions, lipid metabolism disturbance and diabetes. In addition to the data indicating the presence of dyslipidemia and diabetes or insulin resistance in our cohort of chronic hepatitis C patients, we found a series of evidence showing the association between the conditions and HCV infection in mouse models that are transgenic for the HCV genes. In patients with chronic hepatitis C, a significant decrease in the serum levels of total cholesterol and apolipoproteins C2 and C3 was observed compared to those with chronic hepatitis B that were comparable in liver function. In an animal model, C18:1 mono-unsaturated fatty acids were significantly increased in the liver from HCV core gene transgenic mice, which was similarly observed in the liver from human hepatitis C patients. Thus, a disturbance in lipid metabolism was observed in both humans and an HCV mouse model, supporting that it is a specific event in HCV infection. A significant increase in the value of an indicator for homeostasis model assessment of insulin resistance (HOMA-IR), was observed in patients with chronic hepatitis C, even at the very early stage of chronic hepatitis. In the animal model, a marked insulin resistance was exhibited from a very young age in HCV core gene transgenic mice. Insulin resistance observed in the core gene transgenic mice was chiefly due to the shortage of insulin action on the suppression of glucose production in the liver. Thus, the ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes. Insulin resistance may be a critical factor in the pathogenesis of chronic hepatitis C as recently suggested in non-alcoholic steatohepatitis (NASH), along with impairment in lipid metabolism. Our results would provide a clue for further understanding of pathobiology of HCV infection, and may provide an implication for the pathogenesis of NASH.
authors.affiliation: Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113 8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike