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 journalArticle

35 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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    Xu, M., Nagati, J. S., Xie, J., Li, J., Walters, H., Moon, Y. A., Gerard, R. D., Huang, C-L., Comerford, S. A., Hammer, R. E., Horton, J. D., Chen, R., & Garcia, J. A. (2014). An acetate switch regulates stress erythropoiesis. Nature medicine, 20(9), 1018-1026. https://doi.org/10.1038/nm.3587