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

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23 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

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Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kim, M., Neinast, M. D., Frank, A. P., Sun, K., Park, J., Zehr, J. A., Vishvanath, L., Morselli, E., Amelotte, M., Palmer, B. F., Gupta, R. K., Scherer, P. E., & Clegg, D. J. (2014). ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue. Molecular Metabolism, 3(6), 642-651. https://doi.org/10.1016/j.molmet.2014.05.007