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标题：NPC1L1 Facilitates Sphingomyelin Absorption and Regulates Diet-Induced Production of VLDL/LDL-associated S1P
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作者：Yoshihide Yamanashi ; Tappei Takada ; Hideaki Yamamoto 等
期刊名称：Nutrients
电子版ISSN：2072-6643
出版年度：2020
卷号：12
期号：9
页码：2641-2651
DOI：10.3390/nu12092641
出版社：MDPI Publishing
摘要：Niemann-Pick C1-Like 1 (NPC1L1) is a cholesterol importer and target of ezetimibe, a cholesterol absorption inhibitor used clinically for dyslipidemia. Recent studies demonstrated that NPC1L1 regulates the intestinal absorption of several fat-soluble nutrients, in addition to cholesterol. The study was conducted to reveal new physiological roles of NPC1L1 by identifying novel dietary substrate(s). Very low-density lipoprotein and low-density lipoprotein (VLDL/LDL) are increased in Western diet (WD)-fed mice in an NPC1L1-dependent manner, so we comprehensively analyzed the NPC1L1-dependent VLDL/LDL components. Apolipoprotein M (apoM), a binding protein of sphingosine-1-phosphate (S1P: a lipid mediator), and S1P were NPC1L1-dependently increased in VLDL/LDL by WD feeding. S1P is metabolized from sphingomyelin (SM) and SM is abundant in WD, so we focused on intestinal SM absorption. In vivo studies with Npc1l1 knockout mice and in vitro studies with NPC1L1-overexpressing cells revealed that SM is a physiological substrate of NPC1L1. These results suggest a scenario in which dietary SM is absorbed by NPC1L1 in the intestine, followed by SM conversion to S1P and, after several steps, S1P is exported into the blood as the apoM-bound form in VLDL/LDL. Our findings provide insight into the functions of NPC1L1 for a better understanding of sphingolipids and S1P homeostasis.
关键词：absorption; apoM; Niemann-Pick C1-Like 1; sphingomyelin; sphingosine-1-phosphate absorption ; apoM ; Niemann-Pick C1-Like 1 ; sphingomyelin ; sphingosine-1-phosphate