title: Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice.
abstract: OBJECTIVE
  Controversies have arisen from recent mouse studies about the essential role of biliary sterol secretion in reverse cholesterol transport (RCT). The objective of this study was to examine the role of biliary cholesterol secretion in modulating macrophage RCT in Niemann-Pick C1-Like 1 (NPC1L1) liver only (L1(LivOnly)) mice, an animal model that is defective in both biliary sterol secretion and intestinal sterol absorption, and determine whether NPC1L1 inhibitor ezetimibe facilitates macrophage RCT by inhibiting hepatic NPC1L1.
  
  
  RESULTS
  L1(LivOnly) mice were generated by crossing NPC1L1 knockout (L1-KO) mice with transgenic mice overexpressing human NPC1L1 specifically in liver. Macrophage-to-feces RCT was assayed in L1-KO and L1(LivOnly) mice injected intraperitoneally with [(3)H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [(3)H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1(LivOnly) mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [(3)H]-tracer in the neutral sterol fraction in L1(LivOnly) mice. High-density lipoprotein kinetic studies showed that L1(LivOnly) mice compared with L1-KO mice had a significantly reduced fractional catabolic rate without altered hepatic and intestinal uptake of high-density lipoprotein-cholesterol ether.
  
  
  CONCLUSIONS
  In mice lacking intestinal cholesterol absorption, macrophage-to-feces RCT depends on efficient biliary sterol secretion, and ezetimibe promotes macrophage RCT by inhibiting hepatic NPC1L1 function.
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Ou
authors.forename: Hongming
authors.initials: H
authors.lastname: Miao
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Amirfarbod
authors.initials: A
authors.lastname: Yazdanyar
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014316:Tritium
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D014316:Tritium; D002784:Cholesterol; D000069438:Ezetimibe