Division of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland.
Curr Drug Targets. 2011 May;12(5):661-70. doi: 10.2174/138945011795378496.
Bile formation is a key function of the liver and is driven by active secretion of bile salts and other organic compounds into the biliary tree. Bile salts represent the major organic constituent of bile. They are released with bile into the small intestine, where they are almost quantitatively reabsorbed and transported via the portal circulation back to the liver. In the liver, they are taken up into hepatocytes and secreted into bile. This cycling between the liver and the small intestine is called enterohepatic circulation of bile salts. Bile salts are secreted from hepatocytes into the bile by the bile salt export pump BSEP. This step constitutes the rate-limiting step of handling of bile salts in the liver and is the major driving force of the enterohepatic circulation of bile salts. Improper functioning of BSEP leads to an accumulation of bile salts within hepatocytes, where bile salts become cytotoxic. If persistent, accumulation of bile salts in hepatocytes will lead to liver disease. This review summarizes the essential concepts of bile formation and the current knowledge of mechanisms known to impair BSEP function. Finally, it sets the current therapeutic approaches for cholestatic liver disease into perspective to the pathophysiologic mechanisms of impaired BSEP function.
胆汁形成是肝脏的一项关键功能，它是通过主动将胆汁盐和其他有机化合物分泌到胆道系统中驱动的。胆汁盐是胆汁的主要有机成分。它们与胆汁一起排入小肠，几乎被完全重吸收，并通过门静脉循环被运送到肝脏。在肝脏中，它们被摄取到肝细胞中，并分泌到胆汁中。这种在肝脏和小肠之间的循环称为胆汁盐的肠肝循环。胆汁盐由胆汁盐输出泵 BSEP 从肝细胞分泌到胆汁中。这一步骤构成了肝脏中胆汁盐处理的限速步骤，也是胆汁盐肠肝循环的主要驱动力。BSEP 的功能异常会导致胆汁盐在肝细胞内积聚，胆汁盐在肝细胞内具有细胞毒性。如果持续存在，胆汁盐在肝细胞内的积聚将导致肝脏疾病。这篇综述总结了胆汁形成的基本概念以及已知会损害 BSEP 功能的机制的最新知识。最后，它将目前治疗胆汁淤积性肝病的方法与 BSEP 功能受损的病理生理机制联系起来。
