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ER? 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 ? (ER?) 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-1? is ubiquitinated following 17-? estradiol (E2)/ER? mediated Phd3 transcription. Manipulating ER? 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/ER?, PHD3 and HIF-1 in adipose tissues, providing a mechanistic explanation for the protective effect of E2/ER? in adipose tissue.

SUBMITTER: Kim M 

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

REPOSITORIES: biostudies-other

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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]