Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice
Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice
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DOI：
10.1194/jlr.m048629
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发表时间：
2015-07-01
影响因子：
6.5
通讯作者：
Remaley, Alan T.
中科院分区：
文献类型：
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作者：
Thacker, Seth G.;Rousset, Xavier;Remaley, Alan T.
LCAT是一种血浆酶，可分解胆固醇，被认为具有抗动脉粥样硬化的作用，但动物和流行病学研究得出了相互矛盾的结果。为了深入了解LCAT和游离胆固醇（FC）在动脉粥样硬化中的作用，我们检测了LCAT过表达和低表达在食饵诱导的B类清道夫受体成员I缺陷[Scarab（-/-）]小鼠动脉粥样硬化中的作用，该小鼠具有胆固醇酯化的继发性缺陷。Scarab（-/-）xLCAT-null [Lcat（-/-）]小鼠在高脂饮食下HDL-胆固醇降低，FC/总胆固醇（TC）的血浆比率较高（0.88 +/- 0.033），VLDL-胆固醇（VLDL-C）显著升高。圣甲虫（-/-）x LCAT转基因（Tg）小鼠的VLDL-C水平较低，血浆FC/TC比值正常（0.28 +/- 0.005）。Scarab（-/-）x LCAT -Tg小鼠的血浆也显示在体外胆固醇流出期间胆固醇酯化增加，但酯化增加似乎不影响胆固醇流出或胆固醇肝脏摄取的总体速率。与Scarab（-/-）小鼠相比，Scarab（-/-）x LCAT-Tg小鼠也显示主动脉窦动脉粥样硬化减少51%（P < 0.05）。总之，我们证明，增加胆固醇酯化LCAT是动脉粥样硬化保护，最有可能通过其能力，增加HDL水平和减少促动脉粥样硬化载脂蛋白B的脂蛋白颗粒。
LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over-and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab (-/-)] mice, which have a secondary defect in cholesterol esterification. Scarab (-/-) xLCAT-null [Lcat (-/-)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 +/- 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab (-/-) x LCAT -transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 +/- 0.005). Plasma from Scarab (-/-) x LCAT -Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab (-/-) x LCAT -Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab (-/-) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles.