Carboxyl ester lipase expression in macrophages increases cholesteryl ester accumulation and promotes atherosclerosis
Carboxyl ester lipase expression in macrophages increases cholesteryl ester accumulation and promotes atherosclerosis
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DOI：
10.1074/jbc.m502266200
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发表时间：
2005-11-18
影响因子：
4.8
通讯作者：
Hui, DY
中科院分区：
文献类型：
--
作者：
Kodvawala, A;Ghering, AB;Hui, DY
羧酸酯脂肪酶（CEL，也称为胆固醇酯酶或胆汁盐依赖性脂肪酶）是能够以三羟基胆汁盐依赖性方式水解胆固醇酯、三酰基甘油和磷脂但通过胆汁盐非依赖性机制水解神经酰胺和溶血磷脂的脂解酶。尽管CEL主要在胰腺中合成，但在人巨噬细胞中报告了低水平的CEL表达。本研究使用巨噬细胞CEL表达水平与人巨噬细胞中观察到的水平相当的转基因小鼠，以探索巨噬细胞CEL表达的功能作用和生理意义。当细胞在体外基础条件下孵育时，与CEL阴性巨噬细胞相比，CEL转基因小鼠的腹膜巨噬细胞显示[H-3]油酸酯掺入胆固醇[H-3]油酸酯的4倍增加。当挑战乙酰化低密度脂蛋白，胆固醇酯的积累是2.5倍高表达CEL转基因的巨噬细胞。在胆固醇酯积累的差异归因于较低水平的神经酰胺和溶血磷脂酰胆碱在细胞表达细胞比在细胞阴性细胞。当喂养高脂肪/胆固醇饮食时，与动脉粥样硬化易感apoE（-/-）背景饲养的CEL转基因小鼠显示出比没有CEL转基因的apoE（-/-）小鼠高约4倍的动脉粥样硬化病变面积。CEL转基因小鼠血浆致动脉粥样硬化溶血磷脂酰胆碱水平较低，但血浆胆固醇水平和脂蛋白谱在两组之间相似。这些研究证明，巨噬细胞中的CEL表达是促动脉粥样硬化的，其机制是因为其水解神经酰胺和溶血磷脂酰胆碱，促进胆固醇酯化和减少胆固醇流出。
Carboxyl ester lipase (CEL, also called cholesterol esterase or bile salt-dependent lipase) is a lipolytic enzyme capable of hydrolyzing cholesteryl esters, triacylglycerols, and phospholipids in a trihydroxy bile salt-dependent manner but hydrolyzes ceramides and lysophospholipids via bile salt-independent mechanisms. Although CEL is synthesized predominantly in the pancreas, a low level of CEL expression was reported in human macrophages. This study used transgenic mice with macrophage CEL expression at levels comparable with that observed in human macrophages to explore the functional role and physiological significance of macrophage CEL expression. Peritoneal macrophages from CEL transgenic mice displayed a 4-fold increase in [H-3]oleate incorporation into cholesteryl [H-3]oleate compared with CEL-negative macrophages when the cells were incubated under basal conditions in vitro. When challenged with acetylated low density lipoprotein, cholesteryl ester accumulation was 2.5-fold higher in macrophages expressing the CEL transgene. The differences in cholesteryl ester accumulation were attributed to the lower levels of ceramide and lysophosphatidylcholine in CEL-expressing cells than in CEL-negative cells. CEL transgenic mice bred to an atherosclerosis susceptible apoE(-/-) background displayed an approximate 4-fold higher atherosclerotic lesion area than apoE(-/-) mice without the CEL transgene when both were fed a high fat/cholesterol diet. Plasma level of the atherogenic lysophosphatidylcholine was lower in the CEL transgenic mice, but plasma cholesterol level and lipoprotein profile were similar between the two groups. These studies documented that CEL expression in macrophages is pro-atherogenic and that the mechanism is because of its hydrolysis of ceramide and lysophosphatidylcholine in promoting cholesterol esterification and decreasing cholesterol efflux.