| First Author | Zhang X | Year | 2019 |
| Journal | Cell Metab | Volume | 30 |
| Issue | 5 | Pages | 937-951.e5 |
| PubMed ID | 31668872 | Mgi Jnum | J:283696 |
| Mgi Id | MGI:6376838 | Doi | 10.1016/j.cmet.2019.09.016 |
| Citation | Zhang X, et al. (2019) Adipocyte Hypoxia-Inducible Factor 2alpha Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism. Cell Metab 30(5):937-951.e5 |
| abstractText | 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 2alpha (HIF-2alpha) was upregulated after mild cold exposure at 16 degrees C and mediated cold-induced thermogenesis. Adipocyte HIF-2alpha 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-2alpha, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2alpha-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2alpha 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-2alpha as a putative drug target against atherosclerosis. |
