Document Detail


An acetate switch regulates stress erythropoiesis.
MedLine Citation:
PMID:  25108527     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-8-10
Journal Detail:
Title:  Nature medicine     Volume:  -     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-8-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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