N-terminal Domain of NPC1L1 Senses Cholesterol

Niemann-Pick C1-like 1(NPC1L1) plays an essential role in dietary and biliary cholesterol absorption in mammals. NPC1L1 associates with the lipid raft proteins flotillins to form cholesterol-enriched membrane microdomains. The subsequent endocytosis of these microdomains carries bulk of cholesterol into the cell to ensure the efficient cholesterol uptake. However, it’s still a mystery how cholesterol is sensed to initiate this step. Recently, a team of researchers, led by SONG Baoliang at the Shanghai Institute of Biochemistry and Cell Biology, uncovered the mechanism of cholesterol sensing by NPC1L1 and proposed a mechanism for selective cholesterol absorption.

 

In this study, ZHANG Jinghui and GE Liang, under the supervision of Dr. SONG Baoliang, found that the N-terminal domain (NTD) of NPC1L1 directly binds cholesterol and the L216 of this domain is the crucial amino acid for cholesterol binding. Cholesterol binding by NPC1L1-NTD is essential for NPC1L1-mediated cholesterol uptake in both culture cells and mice livers. Loss of the cholesterol binding ability of NTD impairs the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and therefore impedes the NPC1L1 endocytosis and cholesterol uptake. Interestingly, plant sterols do not bind NPC1L1-NTD and cannot induce the endocytosis of NPC1L1, which implies a selective cholesterol absorption mechanism in the small intestine. Another interesting discovery in this work is that 25- and 27- hydroxycholesterol can compete with cholesterol to bind NPC1L1-NTD and inhibit the endocytosis of NPC1L1 through a different mechanism with the commercial cholesterol uptake inhibitor ezetimibe. These findings provide a new way to develop cholesterol absorption inhibitors by searching for compounds binding NPC1L1-NTD.

 

This work entitled “The N-terminal Domain of NPC1L1 Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake” was published online in Journal of Biological Chemistry on May 20th, 2011.

 

This study was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality. (SIBCB)

 

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