An acetate switch regulates stress erythropoiesis

Min Xu, Jason S. Nagati, Jian Xie, Jiwen Li, Holly Walters, Young Ah Moon, Robert D. Gerard, Chou-Long Huang, Sarah A Comerford, Robert E Hammer, Jay D Horton, Rui Chen, Joseph A Garcia

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The hormone erythropoietin (EPO), which is synthesized in the kidney or liver of adult mammals, controls erythrocyte production and is regulated by the stress-responsive transcription factor hypoxia-inducible factor-2 (HIF-2). We previously reported that the lysine acetyltransferase CREB-binding protein (CBP) is required for HIF-2α acetylation and efficient HIF-2-dependent EPO induction during hypoxia. We now show that these processes require acetate-dependent acetyl CoA synthetase 2 (ACSS2). In human Hep3B hepatoma cells and in EPO-generating organs of hypoxic or acutely anemic mice, acetate levels rise and ACSS2 is required for HIF-2α acetylation, CBP-HIF-2α complex formation, CBP-HIF-2α recruitment to the EPO enhancer and efficient induction of EPO gene expression. In acutely anemic mice, acetate supplementation augments stress erythropoiesis in an ACSS2-dependent manner. Moreover, in acquired and inherited chronic anemia mouse models, acetate supplementation increases EPO expression and the resting hematocrit. Thus, a mammalian stress-responsive acetate switch controls HIF-2 signaling and EPO induction during pathophysiological states marked by tissue hypoxia.

Original languageEnglish (US)
Pages (from-to)1018-1026
Number of pages9
JournalNature medicine
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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