孕烷X受体（PXR）对FGF15/19的调控机制及其在抵抗高脂饮食引起肥胖中的作用

Obesity is a high risk factor for the development of a variety of serious diseases such as nonalcoholic fatty liver, diabetes and cardiovascular diseases. Our previous study identified that pregnane X receptor (PXR) knockout mice have high expression levels of fibroblast growth factor 15 (FGF15) in the ileum and resistance to high fat diet-induced obesity. This study will focus on whether PXR plays an important role in bile acids and lipid metabolism by negative regulation of FGF15/19 expression. In the current study, we will employ many methods such as gene reporter assay, PXR knockout, and inhibition of PXR activity to determine the response element for PXR in FGF15/19, investigate the effect of FGF15/19 regulation by PXR on the expression of genes involved in bile acids and lipid metabolism in a high fat diet condition, and analyze the correlation among plasma levels of FGF19, total bile acids levels, compositions of bile acids, and lipid metabolic parameters in obesity populations. This study will clarify the mechanism of FGF15/19 regulation by PXR and resistance to high fat diet-induced obesity, and demonstrate that regulation of FGF15/19 by PXR is an important pathway in the regulation of bile acids and lipid metabolism. We suggest that PXR may represent a potential molecular target for resistance to high fat diet-induced obesity and provide a new possible therapeutic target of prevention and treatment for some metabolism diseases such as obesity.

肥胖是非酒精性脂肪肝、糖尿病、心血管疾病等重大疾病发病的重要危险因素。前期研究发现孕烷X受体（PXR）基因敲除小鼠回肠成纤维细胞生长因子15（FGF15）表达显著增加并抵抗高脂饮食诱导的肥胖。本项目将针对PXR是否通过负调控FGF15/19表达，参与胆汁酸与脂质代谢这一关键问题，通过启动子转录活性、PXR基因敲除、抑制PXR活性等方法，确定PXR在FGF15/19中的调控位点；研究PXR对FGF15/19的调控作用对高脂饮食下胆汁酸与脂质代谢中相关基因表达的影响；分析肥胖人群血浆中FGF19水平与胆汁酸水平及组分、脂代谢指标的相关性，从而阐明PXR对FGF15/19的调控机制及其在抵抗高脂饮食引起肥胖中的作用，证明PXR对FGF15/19的调控是胆汁酸与脂质代谢的重要调控途径，PXR可能是抵抗高脂引起肥胖的一个分子靶标，有望为肥胖等代谢性疾病的预防与诊治等提供科学依据和潜在药物新靶点。

随着经济发展和人们的生活方式发生变化, 肥胖已成为一个全球性的流行病。当前，我国成年居民超重肥胖率已经超过50%，超重和肥胖已成为影响我国居民健康的重要因素。预防和控制肥胖是我国面临的重大公共卫生问题之一。核受体是一类转录因子，在机体的生理代谢过程中发挥着重要作用。本项目探讨核受体在高脂饮食引起的肥胖中的作用机制。通过报告基因启动子荧光素酶活性检测实验发现孕烷X受体(PXR)对FGF15/19的转录表达具有负调控作用。通过高脂饮食实验发现PXR基因敲除小鼠高脂组的体重增加、肝脏内脂质蓄积和甘油三酯水平、血清总胆汁酸水平、肝内胆汁酸合成酶CYP7A1等表达水平均显著低于野生型高脂组，回肠中FGF15表达水平和脂质排出量显著高于野生型高脂组。通过PXR激活剂处理实验发现PXR受其激活剂激活后，上调了野生型小鼠血清总胆汁酸水平、肝内胆汁酸合成酶和转运酶的表达，下调了回肠中FGF15、SHP和IBABP的表达，而ASBT的表达水平增加。通过FXR的激活剂处理实验发现回肠FGF15基因表达量在PXR基因敲除小鼠激活剂组显著高于野生型小鼠激活剂组，肝脏胆汁酸合成酶CYP7A1基因表达量在PXR基因敲除小鼠激活剂组显著低于野生型小鼠激活剂组，显示PXR与FXR之间可能存在相互作用。这些研究发现显示了高脂饮食下，PXR基因缺失促进了FGF15表达，抑制胆汁酸合成酶表达，减少胆汁酸合成，降低脂质吸收，抵抗高脂食物引起的肥胖。PXR通过负调控FGF15表达，参与胆汁酸与脂质代谢，在抵抗高脂饮食诱导的肥胖中具有重要作用，是改善高脂饮食引起肥胖的一个潜在靶点。