Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells
Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells
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DOI：
10.1161/01.atv.18.6.991
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发表时间：
1998-06-01
影响因子：
8.7
通讯作者：
Schotz, MC
中科院分区：
文献类型：
--
作者：
Escary, JL;Choy, HA;Schotz, MC
动脉粥样硬化是由动脉壁中富含胆固醇的病变形成引发的复杂的病理生理过程。巨噬细胞在此过程中发挥着至关重要的作用，因为它们积累大量胆固醇酯（CE）以形成泡沫细胞，从而引发病变的形成并积极参与病变的发展：因此，预防或逆转巨噬细胞泡沫细胞中CE的积累可能会导致免受多种病理效应的保护。在本报告中，我们表明中性胆固醇酯水解酶（nCEH）催化的CE水解可以通过巨噬细胞泡沫细胞中激素敏感性脂肪酶（HSL）的过度表达来调节。在这些研究中，RAW 264.7 细胞（一种小鼠巨噬细胞系）被发现是泡沫细胞形成的合适模型。这些细胞和腹膜巨噬细胞中的 HSL 表达和 nCEH 活性具有可比性。此外，抗体滴定表明，鼠巨噬细胞中的所有 nCEH 活性基本上都是由 HSL 负责的。为了检查 HSL 过表达对泡沫细胞形成的影响，用大鼠 HSL cDNA 稳定转染 RAW 264.7 细胞。在酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 抑制剂存在下，所产生的 HSL 过表达使脂质负载细胞中细胞 CE 的水解增加 2 至 3 倍。此外，添加 cAMP 后，在胆固醇负载、HSL 过表达的细胞中，CE 水解率比对照细胞高 5 倍，并且与对照组细胞相比，仅 9 小时内细胞 CE 就几乎完全水解。
Atherosclerosis is a complex physiopathologic process initiated by the formation of cholesterol-rich lesions in the arterial wall. Macrophages play a crucial role in this process because they accumulate large amounts of cholesterol esters (CEs) to form the foam cells that initiate the formation of the lesion and participate actively in the development of the lesion: Therefore, prevention or reversal of CE accumulation in macrophage foam cells could result in protection from multiple pathological effects. In this report, we show that the CE hydrolysis catalyzed by neutral cholesterol ester hydrolase (nCEH) can be modulated by overexpression of hormone-sensitive lipase (HSL) in macrophage foam cells. For these studies, RAW 264.7 cells, a murine macrophage cell line, were found to be a suitable model of foam cell formation. HSL expression and nCEH activity in these cells and in peritoneal macrophages were comparable. In addition, antibody titration showed that essentially all nCEH activity in murine macrophages was accounted for by HSL. To examine the effect of HSL overexpression on foam cell formation, RAW 264.7 cells were stably transfected with a rat HSL cDNA. The resulting HSL overexpression increased hydrolysis of cellular CEs 2- to 3-fold in lipid-laden cells in the presence of an acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor. Furthermore, addition of cAMP produced a 5-fold higher rate of CE hydrolysis in cholesterol-laden, HSL-overexpressing cells than in control cells and resulted in nearly complete hydrolysis of cellular CEs in only 9 hours, compared with