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

Min Kim, Michael D. Neinast, Aaron P. Frank, Kai Sun, Jiyoung Park, Jordan A. Zehr, Lavanya Vishvanath, Eugenia Morselli, Mason Amelotte, Biff F Palmer, Rana K Gupta, Philipp E Scherer, Deborah J. Clegg

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)642-651
Number of pages10
JournalMolecular Metabolism
Volume3
Issue number6
DOIs
StatePublished - Sep 2014

Keywords

  • Adipose tissue
  • Estrogen
  • Fibrosis
  • Inflammation
  • Metabolic syndrome
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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