C型肝炎病毒E2蛋白對於胰島素阻抗相關分子的影響

The impact of Hepatitis C virus E2 protein on insulin resistance-related molecules in hepatocytes

劉浩毓(Hao-Yu Liu)

指導教授 ： 邱慧玲

中山醫學大學/醫學科技學院/醫學檢驗暨生物技術學系碩士班/碩士(2011年)

https://doi.org/10.6834/CSMU.2011.00028

摘要

臨床上發現C型肝炎病毒感染的併發症中，第二型糖尿病相當常見。研究指出C型肝炎病毒感染與第二型糖尿病主因胰島素阻抗具高度相關性，但確切的機制並不清楚。C型肝炎病毒套膜蛋白E2在感染宿主細胞的過程中扮演很重要的角色，但此E2蛋白是否參與第二型糖尿病的致病機制尚未被探討。有文獻指出，E2蛋白會活化ERK/MAPK訊息傳遞路徑，另一篇文獻也指出，ERK能抑制IRS-1的功能最終導致胰島素阻抗，故推斷E2蛋白極有可能藉由活化ERK而抑制IRS-1的功能，最終導致胰島素阻抗。此研究希望探討E2蛋白是否會導致胰島素阻抗，先前本實驗室結果證實，E2蛋白會抑制胰島素所誘導的Akt/PKB Thr308和GSK3β Ser9磷酸化表現。此實驗透過放射線標的葡萄糖與肝醣分析，觀察到E2蛋白影響肝臟細胞，造成胰島素誘導葡萄糖攝取能力和肝醣合成量降低，但並不影響肝臟中主要表現的GLUT 2表現量。另透過Real time PCR與西方墨點法證明，SOCS3 mRNA、pSTAT3 Tyr705蛋白與SOCS3蛋白表現都會受到E2蛋白影響而增加，且透過免疫沉澱法觀察到，對IRS-1蛋白ubiquitination增加，可能進而造成降解。根據本實驗結果，證實C型肝炎病毒E2蛋白，可促進SOCS3蛋白表現造成IRS-1表現降低。因此可能進而產生胰島素阻抗，並促使第二型糖尿病產生。

關鍵字

C型肝炎E2蛋白 ； 胰島素阻抗

並列摘要

According to clinical finding, hepatitis C virus (HCV) infection may cause some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Insulin resistance is the major cause for type 2 DM. Many evidences suggest that HCV infection may be highly associated with insulin resistance. The mechanisms of type 2 DM which HCV possibly induced are still unclear. HCV E2 protein plays an important role of virus invasion and to induce host immune response. According to the reasons, we want to observe whether HCV E2 protein would associate with insulin resistance. In previous study, we observe HCV E2 protein could impair Akt/PKB Thr308 and GSK3β Ser9 phosphorylation with insulin treatment. In this study, results show that cell insulin-induced glucose uptake and glycogen synthesis both decrease in E2-expression Huh7 cell, but not impair the expression of glucose transporter 2 (GLUT2). On the other hand, our data shown that the protein expression of STAT3 Tyr705 phosphorylation, the mRNA and protein expression of suppressor of cytokine signaling 3 (SOCS3) were increased. The protein expression of insulin receptor substrates-1 (IRS-1) was decreased and could restore by treatment MG132. We also observed the interaction between IRS-1 and ubiquitin was increased. These results possibly lead to insulin resistance. Therefore, HCV E2 protein may involve in the pathogenesis of type 2 DM by inducing insulin resistance.

並列關鍵字

HCV E2 ； insulin resistance

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