Journal article
An acetate switch regulates stress erythropoiesis
Nature medicine, Vol.20(9), pp.1018-1026
09/2014
DOI: 10.1038/nm.3587
PMCID: PMC4159437
PMID: 25108527
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.
Details
- Title: Subtitle
- An acetate switch regulates stress erythropoiesis
- Creators
- Min Xu - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAJason S Nagati - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAJian Xie - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAJiwen Li - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAHolly Walters - Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USAYoung-Ah Moon - Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USARobert D Gerard - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USAChou-Long Huang - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USASarah A Comerford - Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USARobert E Hammer - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USAJay D Horton - Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USARui Chen - 1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.Joseph A Garcia - 1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Department of Medicine, VA North Texas Health Care System, Dallas, Texas, USA.
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.20(9), pp.1018-1026
- DOI
- 10.1038/nm.3587
- PMID
- 25108527
- PMCID
- PMC4159437
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- P01 HL020948 / NHLBI NIH HHS I01 BX000446 / BLRD VA HL20948 / NHLBI NIH HHS HL108104 / NHLBI NIH HHS R01 HL108104 / NHLBI NIH HHS DK79328 / NIDDK NIH HHS P30 DK079328 / NIDDK NIH HHS
- Language
- English
- Date published
- 09/2014
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094309702771
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