男性肝細胞中脂肪新生路徑對雄性激素受體活性之調控研究

De novo lipogenesis in regulating the transcriptional activity of androgen receptor in male hepatocytes

鄭雅紋(Ya-Wen Cheng)

指導教授 ： 陳培哲老師

共同指導教授 ： 葉秀慧老師(Shiou-Hwei Yeh)

國立臺灣大學/醫學院/分子醫學研究所/博士(2016年)

https://doi.org/10.6342/NTU201602728

摘要

近年來,由於全球肥胖盛行率的增加，與肥胖關係密切的非酒精性脂肪性肝疾病逐漸成為已開發國家中最普遍的肝臟疾病之ㄧ。值得注意的是，肥胖或非酒精性脂肪性肝疾病所引發的肝癌有男性高於女性的趨勢，此現象與B型肝炎病毒引發的肝癌好發在男性病患十分相似。因此我們猜測非酒精性脂肪性肝疾病是否像B型肝炎病毒一樣，可能受男性特定因子影響而導致其性別差異。根據研究指出，受醣類刺激而活化的脂肪生成路徑，在非酒精性脂肪性肝疾病的病患中異常增加，推測為影響非酒精性脂肪性肝疾病脂肪變性的主要途徑。本篇論文因此針對脂肪生成是否藉由調控男性特定致癌的轉錄因子，即雄性激素受體的活性，進而促進了男性患者的肝臟病變之可能性加以探討。
利用果糖餵食公鼠以增進肝臟的脂肪生成後，也發現肝臟的雄性激素受體之轉錄活性顯著上升。若將脂肪酸合成酶抑制劑注射到公鼠體內，不僅會抑制果糖對脂肪生成的影響，同時也抑制了雄性激素受體的轉錄活性。另外在細胞實驗中，不論是使用脂肪生成抑制劑或是抑制脂肪生成重要酵素的基因表現，也驗證了脂肪生成對雄性激素受體之轉錄活性的重要性。我們進一步發現脂肪生成是藉由調控二醯基甘油的生成以增進雄性激素受體的轉錄活性。二醯基甘油是生成多種脂肪分子的重要結構，同時也做為訊息傳導分子以影響許多蛋白的功能，例如活化蛋白激酶C。有趣的是，我們發現脂肪生成所產生的特定二醯基甘油亞型，並非經由蛋白激酶C去調控雄性激素受體的轉錄活性，確切調控機制仍有待研究。
總結本篇論文發現了一個脂肪生成調控雄性激素受體的新穎機制，實驗結果將可能做為解釋非酒精性脂肪性肝疾病引發之肝癌中，男性比例高於女性的分子機制之一。

關鍵字

雄性激素受體 ； 脂肪新生路徑 ； 性別

並列摘要

Nonalcoholic fatty liver disease (NAFLD) becomes the most common liver disease in developed countries due to the global epidemic of obesity. Notably, obesity or NAFLD induced hepatocellular carcinoma (HCC) showed male preference, similar to the hepatitis virus induced HCC. It raised a possibility that a male specific factor could be involved in the NAFLD pathogenesis. As the hepatic de novo lipogenesis (DNL) was identified as the major source contributing to the lipid biogenesis in severe metabolic diseases, this study aims to investigate if DNL could via regulating the function of a male specific oncogenic transcriptional factor, the androgen receptor (AR), as a possible mechanism for male prevalence of NAFLD diseases.
The C57BL/6 male mice fed with high carbohydrate diet (HCD) were used to examine the effect of DNL for the transcriptional activity of AR. The results showed HCD-increased DNL could stimulate the transcriptional activity of AR, which could be abolished by the inhibitor for fatty acid synthase (FASN). This has been validated in the cell culture based assay system, showing a decrease of AR activity by suppressing the lipogenesis either by inhibitors for lipogenic enzymes or by knocking down of ACC

並列關鍵字

De novo lipogenesis ； androgen receptor ； gender ； hepatocytes

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