Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism
Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism
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脂肪细胞缺氧诱导因子 2 α 通过促进脂肪神经酰胺分解代谢来抑制动脉粥样硬化
DOI：
10.1016/j.cmet.2019.09.016
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发表时间：
2019-11-05
期刊：
影响因子：
29
通讯作者：
Jiang, Changtao
中科院分区：
文献类型：
--
作者：
Zhang, Xingzhong;Zhang, Yangming;Jiang, Changtao
肥胖引起的脂肪功能障碍是动脉粥样硬化的主要原因。据报道，冷暴露通过调节脂肪功能影响动脉粥样硬化，但其机制尚未完全阐明。在这里，脂肪细胞缺氧诱导因子2 α（HIF-2 α）在16摄氏度的轻度冷暴露后上调，并介导冷诱导的产热。脂肪细胞HIF-2 α缺乏通过增加脂肪神经酰胺水平而加剧了西方饮食诱导的动脉粥样硬化，这削弱了肝细胞胆固醇的消除和产热。从机制上讲，Acer 2，编码碱性神经酰胺酶2的基因，被鉴定为HIF-2 α的新靶基因，触发神经酰胺catalysts。ACER 2的脂肪过表达挽救了脂肪细胞HIF-2 α缺陷诱导的动脉粥样硬化恶化此外，通过HIF脯氨酰羟化酶抑制剂FG-4592激活脂肪HIF-2 α对动脉粥样硬化具有保护作用，伴随着脂肪和血浆神经酰胺和血浆胆固醇水平的降低。这项研究强调了脂肪细胞HIF-2 α作为抗动脉粥样硬化的假定药物靶点。
Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2 alpha (HIF-2 alpha) was upregulated after mild cold exposure at 16 degrees C and mediated cold-induced thermogenesis. Adipocyte HIF-2 alpha deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2 alpha, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2 alpha-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2 alpha by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2 alpha as a putative drug target against atherosclerosis.