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

Biochim Biophys Acta. 2011 Sep;1811(9):549-55. doi: 10.1016/j.bbalip.2011.05.013. Epub 2011 Jun 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Azetidines / pharmacology*
  • Bile / chemistry*
  • Cholesterol / metabolism*
  • Dietary Fats
  • Ezetimibe
  • Feces / chemistry
  • Humans
  • Lipid Metabolism
  • Liver / drug effects*
  • Liver / metabolism*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic


  • Anticholesteremic Agents
  • Azetidines
  • Dietary Fats
  • Membrane Transport Proteins
  • Npc1l1 protein, mouse
  • Cholesterol
  • Ezetimibe