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

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.