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

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.

SUBMITTER: Kim M

PROVIDER: S-EPMC4142394 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

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

Molecular metabolism 20140607 6

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 am ...[more]

PMID: 25161887

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