TY - JOUR
T1 - Ezetimibe inhibits hepatic niemann-pick C1-like 1 to facilitate macrophage reverse cholesterol transport in mice
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
PY - 2013/5
Y1 - 2013/5
N2 - 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.
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.
KW - NPC1L1 reverse cholesterol transport
KW - biliary cholesterol secretion
KW - ezetimibe
KW - fecal neutral sterol excretion
KW - transgenic
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U2 - 10.1161/ATVBAHA.112.301187
DO - 10.1161/ATVBAHA.112.301187
M3 - Article
C2 - 23471229
AN - SCOPUS:84876288577
SN - 1079-5642
VL - 33
SP - 920
EP - 925
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -