1. Academic Validation
  2. Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism

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

  • Cell Metab. 2019 Nov 5;30(5):937-951.e5. doi: 10.1016/j.cmet.2019.09.016.
Xingzhong Zhang 1 Yangming Zhang 1 Pengcheng Wang 1 Song-Yang Zhang 1 Yongqiang Dong 1 Guangyi Zeng 1 Yu Yan 1 Lulu Sun 1 Qing Wu 1 Huiying Liu 1 Bo Liu 1 Wei Kong 1 Xian Wang 1 Changtao Jiang 2
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, PRC; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, PRC.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, PRC; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, PRC. Electronic address: jiangchangtao@bjmu.edu.cn.
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.

Keywords

HIF-2α; adipocyte; atherosclerosis; ceramide.

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