Molecular Biology of Bile Acid Synthesis

说明(申请人提供)：胆汁酸是一种生理性洗涤剂，可产生胆汁流动，促进肠道对脂肪、营养素和维生素的吸收和运输。胆汁酸也是信号分子和炎症介质，可以迅速激活核受体和调节脂肪和葡萄糖代谢的复杂细胞信号通路网络。近年来，胆汁酸反馈抑制胆汁酸合成的分子机制仍不清楚。据认为，胆汁酸激活核受体法尼醇X受体(FXR)，诱导小的异二聚体伙伴(SHP)，从而抑制编码胆固醇71-羟基酶(CYP7A1)的CYP7A1基因的转录，该基因是肝脏胆汁酸合成的第一个限速酶。最近的研究发现了一种由FXR诱导的肠道激素，成纤维细胞生长因子15(FGF15)(在人类中称为FGF19)，它能激活小鼠肝脏中的成纤维细胞生长因子受体4(FGFR4)信号，从而抑制胆汁酸的合成。然而，FXR/FGF19/FGFR4信号通路抑制细胞色素P7A1的机制尚不清楚。核心假设是胆汁酸和FXR通过激活复杂的核受体细胞信号通路网络来调节CYP7A1基因的表达，该网络调节CYP7A1基因的转录，并且微小RNA可能在人类CYP7A1基因的转录后调节中发挥作用。1.研究FGF19/FGFR4对人肝细胞中细胞色素P7A1和胆汁酸合成的调节机制。2.研究microRNA对人肝细胞细胞色素P7A1和胆汁酸合成的调节作用。3.研究细胞色素P7A1在控制肝脏炎症和脂代谢中的作用。本研究的总体目标是阐明胆汁酸激活的核受体和细胞信号通路在肝脏健康和疾病中调节细胞色素P7A1和胆汁酸合成的分子机制。胆汁酸代谢失调会导致淤胆性肝损伤，并导致肝硬变、脂肪变性、血脂异常、糖尿病、肥胖和动脉粥样硬化。针对核受体和信号通路的药物以及miRNA抗组体可能被开发用于治疗代谢性肝病。 与公共健康相关：胆汁酸是吸收营养、运输类脂和类固醇以及处理有毒和外来物质所需的生理性脂分子。胆汁酸也是激活核受体和细胞信号通路的信号分子，以调节脂质和葡萄糖的动态平衡。胆汁酸的合成通过胆汁酸反馈机制在第一限速酶CYP7A1上受到严格调控。胆汁酸反馈性抑制细胞色素P7A1的分子机制尚不清楚。本研究旨在阐明胆汁酸激活的核受体FXR信号在人类细胞色素P7A1基因转录和转录后调控中的分子机制。该项目与肝胆疾病、糖尿病、肥胖和动脉粥样硬化的预防和治疗高度相关。

DESCRIPTION (provided by applicant): Bile acids are physiological detergents that generate bile flow and facilitate intestine absorption and transport of lipids, nutrients and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and a complex network of cell signaling pathways that regulate lipid and glucose metabolism. Despite intense research in recent years, the molecular mechanism of bile acid feedback inhibition of bile acid synthesis remains obscure. It is thought that bile acids activate a nuclear receptor, farnesoid X receptor (FXR) that induces small heterodimer partner (SHP), which inhibits transcription of the CYP7A1 gene encoding cholesterol 71-hydroxylase (CYP7A1), the first and rate-limiting enzyme in bile acid synthesis in the liver. Recent studies have discovered a FXR induced intestinal hormone, fibroblast growth factor 15 (FGF15) (or FGF19 in human) that activates FGF receptor 4 (FGFR4) signaling in mouse liver to inhibit bile acid synthesis. However, the mechanism by which the FXR/FGF19/FGFR4 signaling pathway inhibits CYP7A1 remains unknown. The central hypothesis is that bile acids and FXR regulate CYP7A1 gene expression via activation of an intricate network of nuclear receptor cell signaling pathways that regulate CYP7A1 gene transcription, and that micro RNAs may play a role in post-transcriptional regulation of the human CYP7A1 gene. Three specific aims are: 1. Study the mechanism of FGF19/FGFR4 regulation of CYP7A1 and bile acid synthesis in human hepatocytes. 2. Study microRNA regulation of CYP7A1 and bile acid synthesis in human hepatocytes. 3. Study the role of CYP7A1 in control of hepatic inflammation and lipid metabolism. The overall objective of this study is to elucidate the molecular mechanism of bile acid-activated nuclear receptor and cell signaling pathways in regulation of CYP7A1 and bile acid synthesis in liver health and diseases. Dysregulation of bile acid metabolism causes cholestatic liver injury and contributes to liver cirrhosis, steatosis, dyslipidemia, diabetes, obesity, and atherosclerosis. Drugs targeting to nuclear receptor and signaling pathways, and miRNA antagomirs may be developed for treating metabolic liver diseases. PUBLIC HEALTH RELEVANCE: Bile acids are physiological lipid molecules required for absorption of nutrients, transport of lipid and steroids, and disposal of toxic and xenobiotics. Bile acids also are signaling molecules that activate nuclear receptors and cell signaling pathways to regulate lipid and glucose homeostasis. Bile acid synthesis is tightly regulated at the first and rate-limiting enzyme CYP7A1 by a bile acid feedback mechanism. The molecular mechanism of bile acid feedback inhibition of CYP7A1 remains unclear. The proposed specific aims are designed to elucidate the molecular mechanism of bile acid-activated nuclear receptor FXR signaling in transcription and post- transcriptional regulation of the human CYP7A1 gene. The project is highly relevant to prevention and treatment of hepatobiliary diseases, diabetes, obesity and atherosclerosis.