B 型肝炎病毒X 蛋白質透過與肝臟雄性激素受體途徑交互作用共同調控肝臟新陳代謝作用

Abstract

B 型肝炎病毒（hepatitis B virus, HBV）的感染會造成慢性肝臟發炎，導致肝細胞癌的發生。在B 型肝炎病毒感染造成慢性肝炎的過程中，病毒除了會影響到肝細胞癌的發生外，對肝臟正常的功能也可能會產生影響。由於肝臟是調控新陳代謝作用上非常重要的器官，尤其是脂質和醣類的代謝，因此B 型肝炎病毒的感染有可能會影響到正常的新陳代謝作用，進而影響代謝症候群的發生。在回顧了相關的流行病學的研究後，觀察到B 型肝炎的患者與代謝症候群之間呈現一負相關的現象，並且主要為男性病患較具有此現象，然而C 型肝炎病毒性肝炎反而與代謝症候群呈現正相關，因此與代謝症候群之間的負相關性為B 型肝炎所特有。根據此現象，在本篇論文中提出一個假說：B 型肝炎病毒可能會透過與男性性別相關之特定因子進行交互作用，影響肝臟正常的新陳代謝功能，造成男性B 型肝炎患者比較不容易罹患代謝症候群之現象。在先前的文獻和實驗室先前研究中，發現雄性激素受體（androgen receptor, AR）途徑在肝臟內會調控醣類的代謝，因此推論男性性別相關之特定因子可能為雄性激素受體途徑。此外在實驗室先前的研究中也提出，B 型肝炎病毒的X 蛋白質（HBx）能夠調控雄性激素受體的功能，因此本論文將測試HBx 蛋白是否會透過正向調控雄性激素受體之功能，進而抑制代謝症候群發生之可能。本篇論文使用了HBx 蛋白基因轉殖小鼠（HBx-transgenic mice, HBx-Tg mice）及HBx 蛋白基因轉殖／雄性激素受體基因剔除小鼠（HBx-transgenic/AR knockout mice, HBx-Tg/ARKO mice），進行此假說之測試。首先在雄性HBx-Tg 小鼠中發現HBx 蛋白可能會造成雄性激素受體表現量之增加；此外進一步分析新陳代謝相關的表現型，也發現雄性HBx-Tg 小鼠表現出與雄性雄性激素受體基因轉殖小鼠（AR-Tg mice）類似體重較輕、白色脂肪組織較少及血糖較低之現象，而雄性激素受體基因之剔除會降低這些表現型在HBx-Tg 小鼠之發生。進一步也發現雄性HBx-Tg 小鼠之肝臟中糖質新生作用有受到抑制之現象。本論文結果因此初步支持HBx 蛋白可能透過調控雄性激素受體對糖質新生作用，抑制男性B 肝患者代謝症候群發生之可能。

Infection of hepatitis B virus (HBV) causes persistent chronic hepatitis, which eventually leads to the severe liver diseases, such as cirrhosis and liver cancer. As liver is a key organ in regulating metabolism, especially the carbohydrate and lipid biogenesis, HBV infection might not only affect the carcinogenic process but also affect the hepatic metabolic functions. Several epidemiological studies well documented that HBV patients have significantly lower probability to develop metabolic syndrome, which is more evident in the male than in female patients. Such a correlation however is absent in chronic hepatitis C patients, who are in contrast prone to develop metabolic syndrome. Therefore, it raises a possibility that a specific HBV factor might interact with a male gender specific factor to inhibit metabolic syndrome in male HBV patients. As the clues from literature review and also from our previous studies in hepatic androgen receptor (AR) transgenic and AR knockout mice, the hepatic AR pathway might regulate the glucose metabolism in liver. Moreover, our previous study also identified an interactive effect between HBV X protein (HBx protein) and hepatic AR. Therefore, we proposed to test a hypothesis that HBx could interact with AR in hepatocytes to regulate the glucose metabolism, as a mechanism for decreasing the probability of male hepatitis B patients to develop metabolic syndrome. This hypothesis has been tested in the HBx transgenic (HBx-Tg) and HBx-Tg/AR knockout (HBx-Tg/ARKO) mice. The results first demonstrated that HBx can elevate the hepatic AR protein level in the male HBx-Tg mice. A decrease of body weight in association with the lower white adipose tissues and lower blood glucose levels was further identified in the male HBx-Tg mice, consistent with the phenotypes identified in hepatic AR-Tg male mice. These phenotypes were diminished in the HBx-Tg/ARKO mice and thus were AR pathway dependent. Moreover, we also demonstrated that the gluconeogenesis was significantly decreased in the HBx-Tg male mice. These results thus preliminarily supported that HBx might through elevating hepatic AR to suppress the hepatic gluconeogenesis as one mechanism to decrease the development of metabolic syndrome in male HBV patients.