NPC1L1 Membrane Protein Introduction

Introduction of NPC1L1

NPC1-like intracellular cholesterol transporter 1 (NPC1L1), also known as LDLCQ7, NPC11L1 or SLC65A2, is a multi-pass membrane protein that is encoded by the gene NPC1L1. It is widely expressed in many tissues, including liver, small intestine, kidney, lung, heart, pancreas, testis, pancreas, spleen, gall bladder, muscle, brain, and stomach. The structure of NPC1L1 is characterized by a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif. There are four different isoforms caused by alternative splicing have been found for this gene.

Basic Information of NPC1L1
Protein Name	NPC1-like intracellular cholesterol transporter 1
Gene Name	NPC1L1
Aliases	Niemann-Pick C1-like protein 1
Organism	Homo sapiens (Human)
UniProt ID	Q9UHC9
TransmNPC1L1rane Times	13
Length (aa)	1359
Sequence	MAEAGLRGWLLWALLLRLAQSEPYTTIHQPGYCAFYDECGKNPELSGSLMTLSNVSCLSNTPARKITGDHLILLQKICPRLYTGPNTQACCSAKQLVSLEASLSITKALLTRCPACSDNFVNLHCHNTCSPNQSLFINVTRVAQLGAGQLPAVVAYEAFYQHSFAEQSYDSCSRVRVPAAATLAVGTMCGVYGSALCNAQRWLNFQGDTGNGLAPLDITFHLLEPGQAVGSGIQPLNEGVARCNESQGDDVATCSCQDCAASCPAIARPQALDSTFYLGQMPGSLVLIIILCSVFAVVTILLVGFRVAPARDKSKMVDPKKGTSLSDKLSFSTHTLLGQFFQGWGTWVASWPLTILVLSVIPVVALAAGLVFTELTTDPVELWSAPNSQARSEKAFHDQHFGPFFRTNQVILTAPNRSSYRYDSLLLGPKNFSGILDLDLLLELLELQERLRHLQVWSPEAQRNISLQDICYAPLNPDNTSLYDCCINSLLQYFQNNRTLLLLTANQTLMGQTSQVDWKDHFLYCANAPLTFKDGTALALSCMADYGAPVFPFLAIGGYKGKDYSEAEALIMTFSLNNYPAGDPRLAQAKLWEEAFLEEMRAFQRRMAGMFQVTFMAERSLEDEINRTTAEDLPIFATSYIVIFLYISLALGSYSSWSRVMVDSKATLGLGGVAVVLGAVMAAMGFFSYLGIRSSLVILQVVPFLVLSVGADNIFIFVLEYQRLPRRPGEPREVHIGRALGRVAPSMLLCSLSEAICFFLGALTPMPAVRTFALTSGLAVILDFLLQMSAFVALLSLDSKRQEASRLDVCCCVKPQELPPPGQGEGLLLGFFQKAYAPFLLHWITRGVVLLLFLALFGVSLYSMCHISVGLDQELALPKDSYLLDYFLFLNRYFEVGAPVYFVTTLGYNFSSEAGMNAICSSAGCNNFSFTQKIQYATEFPEQSYLAIPASSWVDDFIDWLTPSSCCRLYISGPNKDKFCPSTVNSLNCLKNCMSITMGSVRPSVEQFHKYLPWFLNDRPNIKCPKGGLAAYSTSVNLTSDGQVLDTVAILSPRLEYSGTISAHCNLYLLDSTSRFMAYHKPLKNSQDYTEALRAARELAANITADLRKVPGTDPAFEVFPYTITNVFYEQYLTILPEGLFMLSLCLVPTFAVSCLLLGLDLRSGLLNLLSIVMILVDTVGFMALWGISYNAVSLINLVSAVGMSVEFVSHITRSFAISTKPTWLERAKEATISMGSAVFAGVAMTNLPGILVLGLAKAQLIQIFFFRLNLLITLLGLLHGLVFLPVILSYVGPDVNPALALEQKRAEEAVAAVMVASCPNHPSRVSTADNIYVNHSFEGSIKGAGAISNFLPNNGRQF

Function of NPC1L1 Membrane Protein

As its name suggests, NPC1L1 mainly plays a critical role in the absorption of intestinal cholesterol by taking up free cholesterol into cells through vesicular endocytosis, maintaining cholesterol homeostasis. What' more, NPC1L1 participates in the transport of multiple lipids and the regulation of lipid metabolism to keep their homeostasis. NPC1L1 deficiency may lead to multiple lipid transport defects. NPC1L1 mutations are thus associated with low-density lipoprotein cholesterol (LDL-C) levels and plasma total cholesterol and coronary heart disease (CHD) risk. It has been reported that NPC1L1 is the direct target of ezetimibe, which can inhibit the absorption of alpha-tocopherol and intestinal cholesterol. NPC1L1 participates at a late step in viral entry via a virion cholesterol-dependent mechanism, suggesting its potential as an antiviral target.

Fig.1 Crystal structure of NPC1L1 NTD. (Kwon, 2011)

Application of NPC1L1 Membrane Protein in Literature

He J., et al. NPC1L1 knockout protects against colitis-associated tumorigenesis in mice. eLife. 2015, 15: 189. PubMed ID: 25881076

This article demonstrates that knockout of NPC1L1 gene protects against colitis-associated tumorigenesis. NPC1L1 knockout can reduce plasma lipid, especially cholesterol, to decrease inflammation.
Kurano M., et al. Hepatic NPC1L1 overexpression ameliorates glucose metabolism in diabetic mice via suppression of gluconeogenesis. Metabolism. 2015, 64(5): 588-96. PubMed ID: 25660144

This article indicates that hepatic NPC1L1 may have different properties of repressing gluconeogenesis via inhibition of FoxO1 pathways by overexpressing NPC1L1 in the livers of lean wild-type mice, db/db mice, and diet-induced obesity mice.
Takada T., et al. NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Sci Transl Med. 2015, 7(275): 275ra23. PubMed ID: 25696002

This article demonstrates that NPC1L1 is a key regulator of a modulator of warfarin therapy and intestinal vitamin K absorption.
Schweitzer M., et al. Characterization of the NPC1L1 gene and proteome from an exceptional responder to ezetimibe. Atherosclerosis. 2016, 246: 78-86. PubMed ID: 26761771

This article gives a detailed analysis of NPC1L1 mutations in an exceptional responder to ezetimibe, showing that NPC1L1 mutations can affect the uptake of cholesterol in the presence of ezetimibe.
Johnson T.A. and Pfeffer S.R. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis. Mol Biol Cell. 2016, 27(11): 1845-52. PubMed ID: 27075173

This article demonstrates that uptake of cholesterol by NPC1L1 does not dependent on endocytosis; additionally, ezetimibe interferes with adsorption activity of NPC1L1's cholesterol but not block internalization of NPC1L1 in RH7777 cells.

NPC1L1 Preparation Options

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Reference

Kwon H J, et al. (2011). The structure of the NPC1L1 N-terminal domain in a closed conformation. PLoS One. 6(4): e18722.

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