hepatitis b virus x protein impairs hepatic insulin signaling through degradation of irs1 and induction of socs3乙肝病毒x蛋白损害肝脏胰岛素信号通过irs1退化和socs3的感应.pdfVIP

Hepatitis B Virus X Protein Impairs Hepatic Insulin Signaling Through Degradation of IRS1 and Induction of SOCS3 KyeongJin Kim, Kook Hwan Kim, JaeHun Cheong* Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea Abstract Background: 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. Methodology: The expressions of insulin signaling components were investigated in HBx-transgenic mice, HBx-constitutive expressing cells, and transiently HBx-transfected cells. Protein and gene expression was examined by Western blot, immunohistochemistry, RT-PCR, and promoter assay. Protein-protein interaction was detected by coimmunoprecipitation. Principal Findings: HBx induced a reduction in the expression of IRS1, and a potent proteasomal inhibitor blocked the downregulation of IRS1. Additionally, HBx enhanced the expression of SOCS3 and induced IRS1 ubiquitination. Also, C/EBPa and STAT3 were involved in the HBx-induced expression of SOCS3. HBx interfered with insulin signaling activation and recovered the insulin-mediated downregulation of gluconeogenic genes. Conclusions/Significance: These results provide direct experimental evidences for the contribution of HBx in the impairment of insulin signaling. Citation: Kim K, Kim KH, Cheong J (2010) Hepatitis B Virus X Protein Impairs Hepatic Insulin Signaling T