11β-HSD1在肝脏脂代谢中的作用及其调控机制研究

Nonalcoholic fatty liver disease (NAFLD) has become China's largest liver disease, its mechanism has not yet been fully elucidated. Recent studies found that 11β hydroxysteroid dehydrogenase type I(11β-HSD1) was involved in the formation of NAFLD, which activated glucocorticoids associated with glucose and lipid metabolism. Previous studies focused on the relationship between the enzyme and glucose metabolism, while the relationship between the enzyme and lipid metabolism is still poorly understood. Our previous data confirmed: targeted intervention of the 11β-HSD1 expression in the liver of mice can significantly alleviate of NAFLD, but the molecular mechanism was unknown. Targeted intervention of 11β-HSD1 showed that fatty acid synthesis pathway major protein, sterol regulatory element-binding protein 1c(SREBP1C), was degraded, while the mRNA did not change. Thus we hypothesized that 11β-HSD1 initiated the ubiquitin- proteasome system's protein quality control on lipid metabolism related protein through activation of glucocorticoid. To verify this hypothesis, we will revalidate clinical specimens to reveal its dynamic variable rule; and using mouse and cell models through adenovirus overexpression, RNA interference and other technical methods, we will focus on key aspects of lipid metabolism and regulatory pathways; from molecular, cellular organization and the overall levels, to explore the gene function in the liver lipid metabolism and regulatory mechanism, and provide the basis for the the NAFLD early diagnosis and gene therapy.

非酒精性脂肪性肝病（NAFLD）现已成为我国第一大肝脏疾病，其发生机制尚未完全阐明。近期发现I型11β羟基类固醇脱氢酶（11β-HSD1）参与了NAFLD的形成，该酶通过活化糖皮质激素而参与糖脂代谢。以往研究多关注该酶与糖代谢的关系，而与脂代谢的关系仍知之甚少。我们前期证实：靶向干预11β-HSD1在小鼠肝脏内的表达可以显著缓解NAFLD，但其分子机制不详。干预11β-HSD1还可引起脂肪酸合成途径主要蛋白SREBP1C蛋白水平降低，而mRNA水平无变化。故我们提出假说：11β-HSD1通过活化糖皮质激素启动泛素化-蛋白酶体系统对脂代谢相关蛋白的调控。为验证此假说，拟利用小鼠和细胞模型，应用腺病毒过表达和RNA干扰等技术手段，围绕脂代谢及调控通路各关键环节，从分子、细胞、组织及整体水平等多个方面探讨11β-HSD1在肝脏脂代谢中的功能及调控机制，为NAFLD早期诊断和基因治疗提供理论依据。

非酒精性脂肪性肝病（NAFLD）现已成为我国第一大肝脏疾病，I 型11β羟基类固醇脱氢酶（11β-HSD1）参与了NAFLD 的形成，通过活化区域性的糖皮质激素而参与糖脂代谢。为深入研究其作用机制，我们构建了肝脏组织特异性转基因小鼠（albumin-11β-HSD1）。研究结果表明，普通饮食4个月即可以形成脂肪肝，长链脂肪酸合成主通路基因SREBP1和FAS蛋白表达上调，极低密度脂蛋白三酰甘油（VLDL-TG）分泌速率降低，肝质量，肝脏与体重比均升高，油红O染色脂质积聚，肝脏脂质含量升高约30%，同时伴随着胰岛素信号通路的钝化。在喂食高脂饮食20周的小鼠实验中11β-HSD1表达升高，肿瘤坏死因子-α (TNFα) 也升高，体内埋泵进一步证实11β-HSD1受TNFα诱导表达升高，肝脏中有脂质沉积，并损害Akt/ FoxO1胰岛素信号通路，细胞学实验中11β-HSD1特异性抑制剂BVT2733可以逆转上述这一变化。本研究为11β-HSD1作为靶标在TNFα诱导的NAFLD和胰岛素抵抗的防治中的应用提供了依据。