Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice.
Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice.
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DOI：
10.1161/atvbaha.112.301187
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Yu L
中科院分区：
文献类型：
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作者：
Xie P;Jia L;Ma Y;Ou J;Miao H;Wang N;Guo F;Yazdanyar A;Jiang XC;Yu L
关于胆固醇分泌在胆固醇逆向转运（RCT）中的重要作用，最近的小鼠研究引起了争议。本研究的目的是检查胆汁胆固醇分泌在调节Niemann-Pick C1-Like 1（NPC 1 L1）仅肝脏（L1 LivOnly）小鼠（胆汁固醇分泌和肠道固醇吸收均存在缺陷的动物模型）巨噬细胞RCT中的作用，并确定NPC 1 L1抑制剂依折麦布是否通过抑制肝脏NPC 1 L1促进巨噬细胞RCT。通过将NPC 1 L1敲除（L1-KO）小鼠与在肝脏中特异性过表达人NPC 1 L1的转基因小鼠杂交产生L1 LivOnly小鼠。在L1-KO和L1 LivOnly小鼠中测定了巨噬细胞-粪便RCT，这些小鼠腹腔内注射了从C57 BL/6小鼠分离的[3 H]-胆固醇标记的腹腔巨噬细胞。在L1 LivOnly小鼠中，通过肝脏过表达NPC 1 L1抑制胆汁固醇分泌，可显著降低[3 H]-胆固醇从原发性腹腔巨噬细胞向胆汁和粪便中中性固醇组分的转运，而不影响胆汁酸组分中的示踪剂排泄。依折麦布给药2周完全恢复了L1 LivOnly小鼠中性固醇组分中[3 H]-示踪剂的胆汁和粪便排泄。HDL动力学研究表明，L1 LivOnly相对L1-KO小鼠具有显著降低的部分分解代谢率，而没有改变肝脏和肠道对HDL-胆固醇醚的摄取。在缺乏肠道胆固醇吸收的小鼠中，巨噬细胞-粪便RCT依赖于有效的胆汁固醇分泌，依折麦布通过抑制肝脏NPC 1 L1功能促进巨噬细胞RCT。
Controversies have arisen from recent mouse studies regarding 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 (L1LivOnly) mice, an animal model that is defective in both biliary sterol secretion and intestinal sterol absorption, and to determine if NPC1L1 inhibitor ezetimibe facilitates macrophage RCT by inhibiting hepatic NPC1L1. L1LivOnly 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 L1LivOnly mice injected intraperitoneally with [3H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [3H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1LivOnly mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [3H]-tracer in the neutral sterol fraction in L1LivOnly mice. HDL kinetic studies showed that L1LivOnly relative L1-KO mice had a significantly reduced fractional catabolic rate without altered hepatic and intestinal uptake of HDL-cholesterol ether. 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.