fg-4592 and Atherosclerosis

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.

Topics: Adipocytes; Adipose Tissue; Alkaline Ceramidase; Animals; Atherosclerosis; Basic Helix-Loop-Helix Transcription Factors; Ceramides; Cholesterol; Cold Temperature; Diet, Western; Gene Knockout Techniques; Glycine; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Signal Transduction; Thermogenesis; Up-Regulation