近日，北京大学姜长涛（Changtao Jiang）及其研究团队发现，脂肪细胞低氧诱导因子2α（HIF-2α）通过促进脂肪神经酰胺分解代谢来抑制动脉粥样硬化。该项研究成果10月24日在线发表于《细胞—代谢》杂志。

研究人员发现，在16°C的轻微寒冷接触后，脂肪细胞HIF-2α上调并介导了冷引起的生热作用。脂肪细胞HIF-2α缺乏通过增加脂肪神经酰胺水平而加剧了西方饮食引起的动脉粥样硬化，从而削弱了肝细胞胆固醇的清除和生热作用。从机制上讲，编码碱性神经酰胺酶2的基因Acer2被鉴定为HIF-2α的新靶基因，触发了神经酰胺分解代谢。脂肪过表达ACER2可以拯救脂肪细胞HIF-2α缺乏所致的动脉粥样硬化加重。

此外，HIF脯氨酰羟化酶抑制剂FG-4592激活脂肪HIF-2α对动脉粥样硬化具有保护作用，并伴有脂肪、血浆神经酰胺和血浆胆固醇水平的降低。这项研究表明脂肪细胞HIF-2α可作为治疗动脉粥样硬化的潜在药物靶标。

据介绍，肥胖引起的脂肪功能障碍是导致动脉粥样硬化的主要因素。据报道，接触寒冷可通过调节脂肪功能来影响动脉粥样硬化，但其机理尚不清楚。

附：英文原文

Title: Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism

Author: Xingzhong Zhang, Yangming Zhang, Pengcheng Wang, Song-Yang Zhang, Yongqiang Dong, Guangyi Zeng, Yu Yan, Lulu Sun, Qing Wu, Huiying Liu, Bo Liu, Wei Kong, Xian Wang, Changtao Jiang

Issue&Volume: 2019/10/24

Abstract: 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 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α 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-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α 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-2α as a putative drug target against atherosclerosis.

DOI: 10.1016/j.cmet.2019.09.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30555-8