The coming of age of our understanding of the enterohepatic circulation of bile salts

法尼甾体X受体 肝肠循环 肝X受体 CYP27A1 胆汁酸 核受体 胆固醇7α羟化酶 CYP8B1 胆盐出口泵 G蛋白偶联胆汁酸受体 胆固醇 小异二聚体伴侣 胆固醇逆向转运 视黄醇X受体 氧甾醇 肝受体同系物-1 内科学 分解代谢 生物 生物化学 脂蛋白 转录因子 运输机 新陈代谢 医学 基因
作者
Richard N. Redinger
出处
期刊:American Journal of Surgery [Elsevier]
卷期号:185 (2): 168-172 被引量:42
标识
DOI:10.1016/s0002-9610(02)01212-6
摘要

Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis.
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