Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver

被引:29
|
作者
Tang, Weiqing [1 ,2 ,3 ]
Jia, Lin [3 ]
Ma, Yinyan [3 ]
Xie, Ping [3 ]
Haywood, Jamie [4 ]
Dawson, Paul A. [4 ]
Li, Jian [1 ,2 ]
Yu, Liqing [3 ]
机构
[1] Peking Univ, Beijing Hosp, Clin Hosp 5, Beijing 100730, Peoples R China
[2] Beijing Hosp, Minist Hlth, Beijing Inst Geriatr, Key Lab Geriatr, Beijing 100730, Peoples R China
[3] Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA
[4] Wake Forest Univ, Sch Med, Dept Internal Med, Gastroenterol Sect, Winston Salem, NC 27157 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2011年 / 1811卷 / 09期
基金
中国国家自然科学基金;
关键词
NPC1L1; Cholesterol absorption; Zetia; Transgenic; PRIMARY HYPERCHOLESTEROLEMIA; ABSORPTION INHIBITOR; DIETARY-CHOLESTEROL; BILE-ACIDS; NPC1L1; ABCG5; HOMEOSTASIS; SECRETION; HUMANS; GENE;
D O I
10.1016/j.bbalip.2011.05.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Niemann-Pick C1-Like 1 (NPC1L1) is highly expressed in the small intestine across mammalian species and is the target of ezetimibe, a potent cholesterol absorption inhibitor. In humans, NPC1L1 is also expressed in the liver. We found that transgenic overexpression of NPC1L1 in the wild-type mouse liver inhibits biliary cholesterol secretion and raises blood cholesterol, which can be reversed by ezetimibe treatment. Unfortunately, the high expression of endogenous NPC1L1 in the intestine hampered a definitive establishment of the role of hepatic NPC1L1 in cholesterol metabolism and ezetimibe action in the liver because intestinal NPC1L1 dramatically influences cholesterol homeostasis and is a target of ezetimibe. To circumvent this obstacle, we crossed liver-specific NPC1L1 transgenic mice to NPC1L1 knockout (L1-KO) mice and created a mouse line expressing no endogenous NPC1L1, but human NPC1L1 in liver only (L1(LivOnly) mice) Compared to L1-KO mice, L1(LivOnly) mice on a 0.2% cholesterol diet showed significantly increased hepatic and plasma cholesterol, and despite a 90% reduction in biliary cholesterol excretion, their fecal cholesterol excretion remained completely unaltered. Remarkably, 4 days of ezetimibe treatment significantly restored biliary cholesterol secretion in L1(LivOnly) mice. These findings demonstrated a direct role of hepatic NPC1L1 in regulating biliary cholesterol excretion and hepatic/blood cholesterol levels, and unequivocally established hepatic NPC1L1 as a target of ezetimibe. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:549 / 555
页数:7
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