饮食胆固醇吸收的研究进展

Progress in the Mechanism of Dietary Cholesterol Absorption

膜蛋白尼曼-匹克C1型类似蛋白1(Niemann-Pick C1 Like 1,NPC1L1)是介导肝脏和小肠细胞从胆汁或食物中吸收胆固醇的关键蛋白质。本文综述了NPC1L1蛋白的结构、功能及其介导肝肠细胞吸收外源胆固醇的分子机制。NPC1L1蛋白与脂筏蛋白Flotillin-1或Flotillin-2结合,在细胞质膜上形成富含胆固醇的膜微结构域,通过clathrin/AP2介导的囊泡内吞机制,将该NPC1L1-Flotillin-Cholesterol膜微结构域内吞运输至细胞内的内吞循环体上;内吞循环体上的胆固醇浓度下降后,NPC1L1-Flotillin复合物则由Cdc42和Myosin Vb.Rab11a.Rab11-FIP2蛋白运输至质膜,以执行下一轮的胆固醇吸收功能。NPC1L1蛋白的N端结构域可特异性结合胆固醇,是NPC1L1-Flotillin-Cholesterol膜微结构域形成所必需的,同时决定了胆固醇吸收的特异性。人群中NPC1L1基因的多态性与胆固醇吸收异常相关。本文还对未来的研究方向进行了探讨。

Niemann Pick C1 Like 1 （NPC1L1）, a polytopic transmembrane protein, is a key protein that mediates the enterohepatic absorption of free cholesterol from diet and bile. In this article, we reviewed the function, structure and working mechanism of NPCILI. NPC1L1 associates with lipid raft proteins Flotillin-1 or Flotillin-2 to form the cholesterol-enriched membrane microdomains on the plasma membrane. The microdomains are endocytosed and transported to the intercellular endocytic recycling compartment （ERC） via vesicular endocytosis pathway mediated by clathrin/AP2 complex. Cholesterol depletion leads to the transport of NPC1L1-Flotillin complex from ERC to plasma membrane, during which Cdc42 and the Myosin Vb. Rablla .Rab11-FIP2 triple complex play crucial roles, and then the plasma membrane-localized NPC1L1 specifically binds exogenous cholesterol via its N-terminal domain （NTD）, which is necessary for the formation of NPC1Ll-flotillin-cholesterol membrane microdomain. Nonsynonymous variants of NPC1L1 in humans are suggested to associate with abnormal cholesterol absorption. We also summarized some of the remaining questions and proposed future directions for this research.