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

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

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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Figure 3

Hepatic expression of NPC1L1 results in a dramatic reduction in biliary cholesterol but not PL and BA.

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Hepatic expression of NPC1L1 results in a dramatic reduction in biliary ...
(A) Concentration of gallbladder cholesterol, PL, and BA in male mice was determined as described in Methods. Molar ratios of each lipid in total biliary lipids were calculated from lipid concentrations. Data are mean ± SEM of 4–6 samples. (B and C) Liver total mRNAs or membrane proteins were prepared as described previously (50) from mice in A, and equal amounts of mRNA or protein from each mouse within a group were pooled (n = 5 per group). Levels of selected mRNAs and proteins were determined by quantitative real-time PCR (B) and by immunoblotting (C), respectively, as described previously (10, 50). RAP was used as the loading control, and human NPC1L1 was immunoblotted with L1Ab for genotype validation. The experiment was repeated twice with different sets of animals, and similar results were obtained. P < 0.05 between * and # groups for each measurement (ANOVA).