Format

Send to

Choose Destination
Nat Med. 2014 Sep;20(9):1018-26. doi: 10.1038/nm.3587. Epub 2014 Aug 10.

An acetate switch regulates stress erythropoiesis.

Author information

1
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5
1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
6
1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Medicine, VA North Texas Health Care System, Dallas, Texas, USA. [3].

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.

PMID:
25108527
PMCID:
PMC4159437
DOI:
10.1038/nm.3587
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center