Ablation of Neutral Cholesterol Ester Hydrolase 1 Accelerates Atherosclerosis
Ablation of Neutral Cholesterol Ester Hydrolase 1 Accelerates Atherosclerosis
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DOI：
10.1016/j.cmet.2009.08.004
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发表时间：
2009-09-02
期刊：
影响因子：
29
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
--
作者：
Sekiya, Motohiro;Osuga, Jun-ichi;Ishibashi, Shun
携带胆固醇酯(CE)的巨噬细胞泡沫细胞是动脉粥样硬化的标志，而细胞内CE的降解是泡沫细胞形成的关键步骤之一。尽管激素敏感脂肪酶(LIPE)和胆固醇酯水解酶(CEH)与羧酸酯酶1(CES1，hCE1)一样被认为是调节巨噬细胞中性CE水解酶(NCEH)活性的酶，但最近的证据表明，其他酶也参与其中。我们最近报道了一个候选基因，中性胆固醇酯水解酶1(Nceh1)。在这里，我们证明了Nceh1的遗传消融促进了泡沫细胞的形成和小鼠动脉粥样硬化的发展。我们进一步证明，Nceh1和LIPE在巨噬细胞中介导了相当程度的NCEH活性；并且共同解释了大部分活性。缺乏Nceh1和Lipe的小鼠以相加的方式加重动脉粥样硬化。因此，Nceh1是治疗动脉粥样硬化的一个有前途的靶点。
Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1 (Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages; and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.