Ezetimibe inhibits hepatic niemann-pick C1-like 1 to facilitate macrophage reverse cholesterol transport in mice

Ping Xie, Lin Jia, Yinyan Ma, Juanjuan Ou, Hongming Miao, Nanping Wang, Feng Guo, Amirfarbod Yazdanyar, Xian Cheng Jiang, Liqing Yu

Research output: Contribution to journalArticle

23 Citations (Scopus)

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) 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. APPROACH AND RESULTS - : L1 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 mice injected intraperitoneally with [H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1 mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [H]-tracer in the neutral sterol fraction in L1 mice. High-density lipoprotein kinetic studies showed that L1 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.

Original languageEnglish (US)
Pages (from-to)920-925
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Macrophages
Sterols
Cholesterol
Liver
Feces
Intestinal Absorption
Peritoneal Macrophages
Ezetimibe
HDL Lipoproteins
Bile Acids and Salts
Inbred C57BL Mouse
Bile
Ether
HDL Cholesterol
Transgenic Mice
Animal Models

Keywords

  • biliary cholesterol secretion
  • ezetimibe
  • fecal neutral sterol excretion
  • NPC1L1 reverse cholesterol transport
  • transgenic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ezetimibe inhibits hepatic niemann-pick C1-like 1 to facilitate macrophage reverse cholesterol transport in mice. / Xie, Ping; Jia, Lin; Ma, Yinyan; Ou, Juanjuan; Miao, Hongming; Wang, Nanping; Guo, Feng; Yazdanyar, Amirfarbod; Jiang, Xian Cheng; Yu, Liqing.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 33, No. 5, 01.05.2013, p. 920-925.

Research output: Contribution to journalArticle

Xie, Ping ; Jia, Lin ; Ma, Yinyan ; Ou, Juanjuan ; Miao, Hongming ; Wang, Nanping ; Guo, Feng ; Yazdanyar, Amirfarbod ; Jiang, Xian Cheng ; Yu, Liqing. / Ezetimibe inhibits hepatic niemann-pick C1-like 1 to facilitate macrophage reverse cholesterol transport in mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2013 ; Vol. 33, No. 5. pp. 920-925.
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AU - Xie, Ping

AU - Jia, Lin

AU - Ma, Yinyan

AU - Ou, Juanjuan

AU - Miao, Hongming

AU - Wang, Nanping

AU - Guo, Feng

AU - Yazdanyar, Amirfarbod

AU - Jiang, Xian Cheng

AU - Yu, Liqing

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AB - 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) 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. APPROACH AND RESULTS - : L1 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 mice injected intraperitoneally with [H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1 mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [H]-tracer in the neutral sterol fraction in L1 mice. High-density lipoprotein kinetic studies showed that L1 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.

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