title: Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver.
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, 4days 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.
authors.affiliation: The 5th Clinical Hospital (Beijing Hospital), Peking University, and Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Da Hua Road, Beijing, 100730, China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Jamie
authors.initials: J
authors.lastname: Haywood
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001646:Bile / Q000737:chemistry*; D002784:Cholesterol / Q000378:metabolism*; D004041:Dietary Fats; D000069438:Ezetimibe; D005243:Feces / Q000737:chemistry; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D004041:Dietary Fats; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D002784:Cholesterol; D000069438:Ezetimibe