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 journalArticle

21 Citations (Scopus)

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 - 2014

Fingerprint

Hypoxia-Inducible Factor 1
Estrogen Receptors
Adipose Tissue
Fibrosis
Up-Regulation
Inflammation
Estrogens
Response Elements
Estradiol
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Kim, M., Neinast, M. D., Frank, A. P., Sun, K., Park, J., Zehr, J. A., ... 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

ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue. / Kim, Min; Neinast, Michael D.; Frank, Aaron P.; Sun, Kai; Park, Jiyoung; Zehr, Jordan A.; Vishvanath, Lavanya; Morselli, Eugenia; Amelotte, Mason; Palmer, Biff F; Gupta, Rana K; Scherer, Philipp E; Clegg, Deborah J.

In: Molecular Metabolism, Vol. 3, No. 6, 2014, p. 642-651.

Research output: Contribution to journalArticle

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 2014, 'ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue', Molecular Metabolism, vol. 3, no. 6, pp. 642-651. https://doi.org/10.1016/j.molmet.2014.05.007
Kim, Min ; Neinast, Michael D. ; Frank, Aaron P. ; Sun, Kai ; Park, Jiyoung ; Zehr, Jordan A. ; Vishvanath, Lavanya ; Morselli, Eugenia ; Amelotte, Mason ; Palmer, Biff F ; Gupta, Rana K ; Scherer, Philipp E ; Clegg, Deborah J. / ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue. In: Molecular Metabolism. 2014 ; Vol. 3, No. 6. pp. 642-651.
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