Bernsmeier Christine, Duong Francois H T, Christen Verena, Pugnale Paolo, Negro Francesco, Terracciano Luigi, Heim Markus H
Department of Biomedicine, Division of Gastroenterology and Hepatology, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
J Hepatol. 2008 Sep;49(3):429-40. doi: 10.1016/j.jhep.2008.04.007. Epub 2008 Apr 30.
BACKGROUND/AIMS: Hepatitis C virus (HCV) infection disturbs glucose and lipid metabolism contributing to the development of liver steatosis, insulin resistance and type 2 diabetes mellitus. On the other hand, insulin resistance and steatosis have been found to be associated with increased rates of fibrosis progression and lower rates of response to interferon therapy in chronic hepatitis C (CHC). The molecular mechanisms contributing to insulin resistance in CHC are not well understood. We have shown previously that protein phosphatase 2A (PP2A) is over-expressed in biopsies from patients with CHC. In this study, we tested if PP2A over-expression leads to insulin resistance.
We studied insulin signalling in cell lines that allow the regulated over-expression of HCV proteins and of the PP2A catalytic subunit (PP2Ac). Insulin signalling and PP2Ac expression were also studied in HCV transgenic mice and in liver biopsies from patients with CHC.
Over-expression of PP2Ac in cells inhibited insulin signalling by dephosphorylation of PKB/Akt. PP2Ac over-expression and impaired insulin signalling were found in the liver of HCV transgenic mice and in liver biopsies of patients with CHC.
HCV-induced over-expression of PP2A in the liver contributes to the pathogenesis of insulin resistance in patients with CHC.
背景/目的：丙型肝炎病毒（HCV）感染会扰乱葡萄糖和脂质代谢，促使肝脂肪变性、胰岛素抵抗和2型糖尿病的发生。另一方面，已发现胰岛素抵抗和脂肪变性与慢性丙型肝炎（CHC）患者的纤维化进展加快及干扰素治疗反应率降低有关。CHC中导致胰岛素抵抗的分子机制尚未完全明确。我们之前已表明，蛋白磷酸酶2A（PP2A）在CHC患者的活检组织中过度表达。在本研究中，我们检测了PP2A的过度表达是否会导致胰岛素抵抗。
我们在能够调控HCV蛋白和PP2A催化亚基（PP2Ac）过度表达的细胞系中研究胰岛素信号传导。还在HCV转基因小鼠和CHC患者的肝活检组织中研究了胰岛素信号传导和PP2Ac表达。
细胞中PP2Ac的过度表达通过使蛋白激酶B/蛋白激酶B（PKB/Akt）去磷酸化而抑制胰岛素信号传导。在HCV转基因小鼠的肝脏和CHC患者的肝活检组织中发现了PP2Ac的过度表达及胰岛素信号传导受损。
HCV诱导的肝脏中PP2A过度表达促成了CHC患者胰岛素抵抗的发病机制。
