| First Author | Tang W | Year | 2011 |
| Journal | Biochim Biophys Acta | Volume | 1811 |
| Issue | 9 | Pages | 549-55 |
| PubMed ID | 21683156 | Mgi Jnum | J:177621 |
| Mgi Id | MGI:5295557 | Doi | 10.1016/j.bbalip.2011.05.013 |
| Citation | Tang W, et al. (2011) Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver. Biochim Biophys Acta 1811(9):549-55 |
| abstractText | 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. |
