Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 549-555 |
| Number of pages | 7 |
| Journal | Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids |
| Volume | 1811 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2011 |
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Keywords
- Cholesterol absorption
- NPC1L1
- Transgenic
- Zetia
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver. / Tang, Weiqing; Jia, Lin; Ma, Yinyan; Xie, Ping; Haywood, Jamie; Dawson, Paul A.; Li, Jian; Yu, Liqing.
In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1811, No. 9, 01.09.2011, p. 549-555.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver
AU - Tang, Weiqing
AU - Jia, Lin
AU - Ma, Yinyan
AU - Xie, Ping
AU - Haywood, Jamie
AU - Dawson, Paul A.
AU - Li, Jian
AU - Yu, Liqing
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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.
KW - Cholesterol absorption
KW - NPC1L1
KW - Transgenic
KW - Zetia
UR - http://www.scopus.com/inward/record.url?scp=79960496099&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960496099&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2011.05.013
DO - 10.1016/j.bbalip.2011.05.013
M3 - Article
C2 - 21683156
AN - SCOPUS:79960496099
VL - 1811
SP - 549
EP - 555
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
SN - 1388-1981
IS - 9
ER -