Research Article: Hepatitis B Virus X Protein Impairs Hepatic Insulin Signaling Through Degradation of IRS1 and Induction of SOCS3

Date Published: March 23, 2010

Publisher: Public Library of Science

Author(s): KyeongJin Kim, Kook Hwan Kim, JaeHun Cheong, Dong-Yan Jin.

Abstract: Hepatitis B virus (HBV) is a major cause of chronic liver diseases, and frequently results in hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The role of HCV in associations with insulin signaling has been elucidated. However, the pathogenesis of HBV-associated insulin signaling remains to be clearly characterized. Therefore, we have attempted to determine the mechanisms underlying the HBV-associated impairment of insulin signaling.

Partial Text: An estimated 2 billion people worldwide are currently infected with the hepatitis B virus (HBV), which results in chronic hepatitis, cirrhosis, and in certain instances, hepatocellular carcinoma (HCC) [1], [2]. Among the four proteins originating from the HBV genome, such as the polymerase, surface, core, and HBx proteins, hepatitis B virus X, a small 154-amino acid protein, is a multifunctional regulator which modulates a variety of host processes via interaction with virus and host factors [3], [4]. Previous reports have demonstrated that HBx proteins induce the expression of lipid synthesis-related genes and inflammation in transgenic mice [5], [6], [7]. Generally, hepatic steatosis, the accumulation of lipid in the hepatocytes, has negative effects on liver functions, which may be resulted or caused by inflammation. NF-κB is activated in the hepatocytes and cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) are overproduced in fatty liver. These proinflammatory cytokines can participate in the attenuation of insulin signaling [8], [9], [10].

As it has been estimated that approximately 53% of HCC cases worldwide are associated with HBV, research into HBV infection has been focused principally on the pathogenesis of HCC. However, it is possible that the deregulation of a number of metabolic components in HBV-infected livers may contribute to the pathogenesis of advanced liver diseases. Among the four proteins that originate from the HBV genome, such as polymerase, surface, core, and HBx proteins, HBx is reported to be associated with HBV-related pathogenesis [46]. Previous reports have demonstrated that HBx proteins induce fatty liver diseases via regulating of the expression of lipid synthesis-related genes in transgenic mice and hepatic cells [5], [6], and hepatic inflammation is observed frequently in HBx-transgenic mice [6]. Some reports are demonstrated that patients with HBV infection show an association between steatosis and insulin resistance, with its clinical concomitants of obesity, hyperglycemia, and hypertriglyceridemia [47].



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