Molecular Biology of Bile Acid Synthesis

描述（由申请人提供）：胆汁酸是生理性洗涤剂，产生胆汁流动，促进肠道吸收和运输脂质、营养物质和维生素。胆汁酸也是一种信号分子和炎症因子，可以快速激活核受体和调节脂质和葡萄糖代谢的复杂细胞信号通路网络。尽管近年来研究不断深入，但胆汁酸反馈抑制胆汁酸合成的分子机制尚不清楚。据认为，胆汁酸激活核受体，法尼索酮X受体（FXR），诱导小异二聚体伴侣（SHP），抑制编码胆固醇71-羟化酶（CYP7A1）的CYP7A1基因的转录，CYP7A1是肝脏中胆汁酸合成的第一酶和限速酶。最近的研究发现，FXR诱导的肠道激素，成纤维细胞生长因子15 (FGF15)（或人类FGF19），激活小鼠肝脏中FGF受体4 （FGFR4）信号，抑制胆汁酸合成。然而，FXR/FGF19/FGFR4信号通路抑制CYP7A1的机制尚不清楚。核心假设是胆酸和FXR通过激活一个复杂的核受体细胞信号通路网络来调节CYP7A1基因的表达，从而调节CYP7A1基因的转录，并且微rna可能在人类CYP7A1基因的转录后调控中发挥作用。三个具体目标是：1。研究FGF19/FGFR4调控人肝细胞CYP7A1和胆汁酸合成的机制。2. 研究人肝细胞中CYP7A1和胆汁酸合成的microRNA调控。3. 研究CYP7A1在肝脏炎症及脂质代谢控制中的作用。本研究的总体目的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控CYP7A1和胆汁酸合成的分子机制。胆汁酸代谢失调导致胆汁淤积性肝损伤，并导致肝硬化、脂肪变性、血脂异常、糖尿病、肥胖和动脉粥样硬化。靶向核受体和信号通路的药物以及miRNA拮抗剂可能被开发用于治疗代谢性肝病。

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.