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Citations to this article

Hepatic Niemann-Pick C1–like 1 regulates biliary cholesterol concentration and is a target of ezetimibe
Ryan E. Temel, … , Lisa-Mari Nilsson, Liqing Yu
Ryan E. Temel, … , Lisa-Mari Nilsson, Liqing Yu
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1968-1978. https://doi.org/10.1172/JCI30060.
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Research Article Hepatology Article has an altmetric score of 9

Hepatic Niemann-Pick C1–like 1 regulates biliary cholesterol concentration and is a target of ezetimibe

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Abstract

Niemann-Pick C1–like 1 (NPC1L1) is required for cholesterol absorption. Intestinal NPC1L1 appears to be a target of ezetimibe, a cholesterol absorption inhibitor that effectively lowers plasma LDL-cholesterol in humans. However, human liver also expresses NPC1L1. Hepatic function of NPC1L1 was previously unknown, but we recently discovered that NPC1L1 localizes to the canalicular membrane of primate hepatocytes and that NPC1L1 facilitates cholesterol uptake in hepatoma cells. Based upon these findings, we hypothesized that hepatic NPC1L1 allows the retention of biliary cholesterol by hepatocytes and that ezetimibe disrupts hepatic function of NPC1L1. To test this hypothesis, transgenic mice expressing human NPC1L1 in hepatocytes (L1-Tg mice) were created. Hepatic overexpression of NPC1L1 resulted in a 10- to 20-fold decrease in biliary cholesterol concentration, but not phospholipid and bile acid concentrations. This decrease was associated with a 30%–60% increase in plasma cholesterol, mainly because of the accumulation of apoE-rich HDL. Biliary and plasma cholesterol concentrations in these animals were virtually returned to normal with ezetimibe treatment. These findings suggest that in humans, ezetimibe may reduce plasma cholesterol by inhibiting NPC1L1 function in both intestine and liver, and hepatic NPC1L1 may have evolved to protect the body from excessive biliary loss of cholesterol.

Authors

Ryan E. Temel, Weiqing Tang, Yinyan Ma, Lawrence L. Rudel, Mark C. Willingham, Yiannis A. Ioannou, Joanna P. Davies, Lisa-Mari Nilsson, Liqing Yu

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 Total
Citations: 4 2 5 9 8 7 7 7 6 7 6 14 10 13 9 23 9 9 1 156
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Citations to this article in year 2016 (7)

Title and authors Publication Year
GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway
M Li, X Meng, J Xu, X Huang, H Li, G Li, S Wang, Y Man, W Tang, J Li
Scientific Reports 2016
Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux
D Meriwether, D Sulaiman, A Wagner, V Grijalva, I Kaji, KJ Williams, L Yu, S Fogelman, C Volpe, SJ Bensinger, GM Anantharamaiah, I Shechter, AM Fogelman, ST Reddy
Journal of lipid research 2016
Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis
TA Johnson, SR Pfeffer
Molecular biology of the cell 2016
Sterol O-Acyltransferase 2-Driven Cholesterol Esterification Opposes Liver X Receptor-Stimulated Fecal Neutral Sterol Loss
M Warrier, J Zhang, K Bura, K Kelley, MD Wilson, LL Rudel, JM Brown
Lipids 2016
The NPC1L1 Polymorphism 1679C>G Is Associated with Gallstone Disease in Chinese Patients
J Wu, W Cui, Q Cai, J Fei, SD Zhang, TQ Han, H Hu, ZY Jiang, L Yu
PloS one 2016
Serum Plant Sterols Associate with Gallstone Disease Independent of Weight Loss and Non-Alcoholic Fatty Liver Disease
P Käkelä, V Männistö, I Ilves, M Vaittinen, MM Tauriainen, M Eskelinen, H Gylling, H Paajanen, J Pihlajamäki
Obesity Surgery 2016
The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus-driven hepatic steatosis
D Ferguson, J Zhang, MA Davis, RN Helsley, LL Vedin, RG Lee, RM Crooke, MJ Graham, DS Allende, P Parini, JM Brown
Journal of lipid research 2016

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