Sudhop Thomas, Lütjohann Dieter, von Bergmann Klaus
Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Pharmacol Ther. 2005 Mar;105(3):333-41. doi: 10.1016/j.pharmthera.2004.10.011. Epub 2004 Dec 9.
Recent insights in the role of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8, the discovery of ezetimibe, the first approved direct cholesterol absorption inhibitor, as well as the identification of Niemann-Pick C1 Like 1 (NPC1L1) protein as sterol transporter in the gut, focused attention on sterol transport processes in the small intestine and the liver. The identification of defective structures in the ABCG5 or ABCG8 transporters in patients with the rare disease of sitosterolemia elucidated their role as sterol efflux pumps regulating at least in parts the intestinal sterol absorption and the hepatic sterol output. ABCG5 and ABCG8 themselves are regulated by cholesterol via liver X receptors (LXRs), which are also activated by oxysterols and some derivatives of plant sterols. NPC1L1 could recently be identified as a major sterol transporter for the intestinal uptake of cholesterol as well as plant sterols. Studies in NPC1L1 knockout mice indicate that this transporter is essential for the intestinal uptake of sterols and that NPC1L1 might also be involved in the mechanism of action of ezetimibe. However, studies with photoreactive cholesterol as well as with photoreactive ezetimibe analogues suggest that other processes might also be involved in the mechanism of action of ezetimibe.
近期对ATP结合盒（ABC）转运蛋白ABCG5和ABCG8作用的深入了解、首个获批的直接胆固醇吸收抑制剂依折麦布的发现，以及将尼曼-匹克C1样1（NPC1L1）蛋白鉴定为肠道中的固醇转运蛋白，使得人们将注意力集中在小肠和肝脏中的固醇转运过程上。在患有罕见的谷甾醇血症的患者中，ABCG5或ABCG8转运蛋白存在缺陷结构，这阐明了它们作为固醇流出泵的作用，至少在一定程度上调节肠道固醇吸收和肝脏固醇输出。ABCG5和ABCG8自身受肝脏X受体（LXRs）的胆固醇调节，肝脏X受体也可被氧化固醇和一些植物固醇衍生物激活。最近，NPC1L1被确定为肠道吸收胆固醇以及植物固醇的主要固醇转运蛋白。对NPC1L1基因敲除小鼠的研究表明，该转运蛋白对于肠道吸收固醇至关重要，并且NPC1L1可能也参与依折麦布的作用机制。然而，使用光反应性胆固醇以及光反应性依折麦布类似物的研究表明，依折麦布的作用机制可能还涉及其他过程。
