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ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue.

Research paper by Min M Kim, Michael D MD Neinast, Aaron P AP Frank, Kai K Sun, Jiyoung J Park, Jordan A JA Zehr, Lavanya L Vishvanath, Eugenia E Morselli, Mason M Amelotte, Biff F BF Palmer, Rana K RK Gupta, Philipp E PE Scherer, Deborah J DJ Clegg

Indexed on: 28 Aug '14Published on: 28 Aug '14Published in: Molecular Metabolism



Abstract

Hypoxia Inducible Factor 1 (HIF-1) promotes fibrosis and inflammation in adipose tissues, while estrogens and Estrogen Receptor α (ERα) have the opposite effect. Here we identify an Estrogen Response Element (ERE) in the promoter of Phd3, which is a negative regulatory enzyme of HIF-1, and we demonstrate HIF-1α is ubiquitinated following 17-β estradiol (E2)/ERα mediated Phd3 transcription. Manipulating ERα in vivo increases Phd3 transcription and reduces HIF-1 activity, while addition of PHD3 ameliorates adipose tissue fibrosis and inflammation. Our findings outline a novel regulatory relationship between E2/ERα, PHD3 and HIF-1 in adipose tissues, providing a mechanistic explanation for the protective effect of E2/ERα in adipose tissue.