N-terminal domain of the cholesterol transporter Niemann Pick Cl-like 1 (NPC1L1) is essential for oc-tocopherol transport
N-terminal domain of the cholesterol transporter Niemann Pick Cl-like 1 (NPC1L1) is essential for oc-tocopherol transport
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DOI：
10.1016/j.bbrc.2017.03.065
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发表时间：
2017-04-29
影响因子：
3.1
通讯作者：
Morita, Tetsuo
中科院分区：
文献类型：
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作者：
Kamishikiryo, Jun;Haraguchi, Misaki;Morita, Tetsuo
胆固醇和α-生育酚都是人类和动物必需的亲脂性营养素。虽然胆固醇过量会导致严重的问题，如冠心病，但它是细胞膜的必要组成部分，是类固醇激素和胆汁酸生物合成的前体。Niemann Pick Cl-样1（NPC 1 L1）是一种胆固醇转运蛋白，在人类的小肠和肝脏中高度表达，并在胆固醇稳态中起重要作用。胆固醇促进NPC 1 L1内吞作用，这是胆固醇摄取的早期步骤。此外，α-生育酚是维生素E最活跃的形式，足量的维生素E对健康至关重要。据报道，NPC 1 L1介导α-生育酚吸收;然而，该过程的机制尚不清楚。在这项研究中，我们发现用α-生育酚处理稳定表达NPC 1 L1-GFP的细胞可促进NPC 1 L1的内吞作用，而NPC 1 L1抑制剂依折麦布可有效防止α-生育酚诱导的NPC 1 L1的内吞作用。胆固醇与NPC 1 L1的N-末端结构域（NTD）结合（NPC 1 L1-NTD）对于NPC 1 L1介导的胆固醇吸收至关重要。我们发现，α-生育酚竞争性结合NPC 1 L1-NTD与胆固醇。此外，当细胞稳定表达NPC 1 L1 ANTD-GFP时，α-生育酚不能诱导NPC 1 L1 ANTD的内吞作用。总之，这些结果表明，NPC 1 L1通过其NTD识别α-生育酚，并通过与胆固醇吸收相同的机制介导α-生育酚吸收。(C)2017爱思唯尔公司All rights reserved.
Both cholesterol and a-tocopherol are essential lipophilic nutrients for humans and animals. Although cholesterol in excess causes severe problems such as coronary heart disease, it is a necessary component of cell membranes and is the precursor for the biosynthesis of steroid hormones and bile acids. Niemann Pick Cl-like 1 (NPC1L1) is a cholesterol transporter that is highly expressed in the small intestine and liver in humans and plays an important role in cholesterol homeostasis. Cholesterol promotes NPC1L1 endocytosis, which is an early step in cholesterol uptake. Furthermore, alpha-tocopherol is the most active form of vitamin E, and sufficient amounts of vitamin E are critical for health. It has been reported that NPC1L1 mediates alpha-tocopherol absorption; however, the mechanisms underlying this process are unknown. In this study, we found that treatment of cells that stably express NPC1L1-GFP with alpha-tocopherol promotes NPC1L1 endocytosis, and the NPC1L1 inhibitor, ezetimibe, efficiently prevents the alpha-tocopherol-induced endocytosis of NPC1L1. Cholesterol binding to the N-terminal domain (NTD) of NPC1L1 (NPC1L1-NTD) is essential for NPC1L1-mediated cholesterol absorption. We found that alpha-tocopherol competitively binds NPC1L1-NTD with cholesterol. Furthermore, when cells stably expressed NPC1L1ANTD-GFP, alpha-tocopherol could not induce the endocytosis of NPC1L1ANTD. Taken together, these results demonstrate that NPC1L1 recognizes alpha-tocopherol via its NTD and mediates alpha-tocopherol uptake through the same mechanism as cholesterol absorption. (C) 2017 Elsevier Inc. All rights reserved.