Abstract
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 NPC1L1.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.Rab11a.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 NPC1L1-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.
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