The Critical Role of Neutral Cholesterol Ester Hydrolase 1 in Cholesterol Removal From Human Macrophages
The Critical Role of Neutral Cholesterol Ester Hydrolase 1 in Cholesterol Removal From Human Macrophages
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DOI：
10.1161/circresaha.110.226613
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发表时间：
2010-11-26
影响因子：
20.1
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
--
作者：
Igarashi, Masaki;Osuga, Jun-ichi;Ishibashi, Shun
原理：细胞内胆固醇酯（CE）的水解是巨噬细胞泡沫细胞中胆固醇逆向转运的关键步骤。我们最近发现，中性胆固醇酯水解酶（Nceh）1和激素敏感脂肪酶（Lipe）是小鼠巨噬细胞中这一过程的关键调节因子。然而，目前尚不清楚哪种酶在人类巨噬细胞和动脉粥样硬化中起关键作用。目的：鉴定人巨噬细胞中负责CE水解的酶，并测定其在人动脉粥样硬化中的表达。方法和结果：我们比较了NCEH1、LIPE和胆固醇酯水解酶（CES1）在人单核细胞源性巨噬细胞（HMMs）中的表达，并检测了每种酶在胆固醇运输中的抑制或过表达的影响。在hmm分化过程中，NCEH1的表达模式与中性CE水解酶活性相似。人NCEH1的过表达增加了CE的水解，从而刺激THP-1巨噬细胞的胆固醇动员。NCEH1的敲低特异性地降低了中性CE水解酶的活性。药物抑制NCEH1也增加了HMMs细胞CE。相比之下，在hmm中几乎检测不到LIPE，其抑制并未降低中性CE水解酶活性。CES1的过表达和敲低均不影响中性CE水解酶活性。NCEH1在人动脉粥样硬化病变的cd68阳性巨噬细胞泡沫细胞中表达。结论：NCEH1在人动脉粥样硬化病变中表达，在人巨噬细胞泡沫细胞CE的水解中起关键作用，从而参与了人动脉粥样硬化中胆固醇逆向转运的初始部分。（Circ Res. 2010;107:1387-1395。）
Rationale: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis.Objective: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis.Methods and Results: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions.Conclusions: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis. (Circ Res. 2010;107:1387-1395.)