ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue.
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.
Kim, M; Neinast, MD; Frank, AP; Sun, K; Park, J; Zehr, JA; Vishvanath, L; Morselli, E; Amelotte, M; Palmer, BF; Gupta, RK; Scherer, PE; Clegg, DJ
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