title: An acetate switch regulates stress erythropoiesis.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Nagati
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Walters
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Moon
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.affiliation: 1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: 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].
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D015687:Cell Hypoxia; D004920:Erythropoiesis; D004921:Erythropoietin / Q000235:genetics; D051379:Mice; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000085:Acetates; C485502:HIF-2 protein, mouse; D014157:Transcription Factors; D004921:Erythropoietin
references.citation: Mech Dev. 1997 Apr;63(1):51-60
references.pmid: 9178256
references.citation: Nat Genet. 2003 Dec;35(4):331-40
references.pmid: 14608355
references.citation: J Comp Neurol. 2010 Aug 1;518(15):2952-77
references.pmid: 20533355
references.citation: J Exp Med. 2014 Feb 10;211(2):181-8
references.pmid: 24493804
references.citation: J Clin Invest. 2014 Feb;124(2):553-63
references.pmid: 24435044
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13212-7
references.pmid: 16141338
references.citation: Life Sci. 1995;57(11):1067-76
references.pmid: 7658914
references.citation: J Neurosci. 2006 Sep 13;26(37):9471-81
references.pmid: 16971531
references.citation: J Biol Chem. 2012 Aug 31;287(36):30800-11
references.pmid: 22807441
references.citation: Biochem J. 1987 May 1;243(3):821-7
references.pmid: 3663102
references.citation: Mech Dev. 2002 Jul;115(1-2):139-41
references.pmid: 12049778
references.citation: J Neurosci. 1998 Jul 15;18(14):5225-33
references.pmid: 9651205
references.citation: Biochim Biophys Acta. 1971 Oct 5;248(1):24-33
references.pmid: 4334748
references.citation: Int J Biochem. 1992 Jul;24(7):1029-31
references.pmid: 1397495
references.citation: Genes Dev. 2001 Oct 15;15(20):2675-86
references.pmid: 11641274
references.citation: Cochrane Database Syst Rev. 2012 Dec 12;12:CD003407
references.pmid: 23235597
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
references.pmid: 7539918
references.citation: Blood. 2009 Sep 3;114(10):2015-9
references.pmid: 19494350
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4273-8
references.pmid: 9113979
references.citation: J Cell Biochem. 2004 Jun 1;92(3):491-501
references.pmid: 15156561
references.citation: Blood. 2005 Apr 15;105(8):3133-40
references.pmid: 15626745
references.citation: Exp Hematol. 2005 Nov;33(11):1263-70
references.pmid: 16263408
references.citation: Contrib Nephrol. 1994;108:114-20
references.pmid: 8039392
references.citation: Blood. 2010 Oct 21;116(16):3039-48
references.pmid: 20628150
references.citation: Adv Enzyme Regul. 1988;27:313-43
references.pmid: 2854950
references.citation: J Clin Invest. 2007 Apr;117(4):1068-77
references.pmid: 17404621
references.citation: Trends Endocrinol Metab. 2013 Apr;24(4):190-9
references.pmid: 23218687
references.citation: Hepatology. 2000 Feb;31(2):255-60
references.pmid: 10655244
references.citation: J Clin Invest. 1997 Oct 15;100(8):2115-24
references.pmid: 9329978
references.citation: Physiology (Bethesda). 2009 Apr;24:97-106
references.pmid: 19364912
references.citation: Biochem J. 1985 Feb 1;225(3):761-86
references.pmid: 3919712
references.citation: Genes Dev. 2002 Jun 15;16(12):1466-71
references.pmid: 12080085
references.citation: Blood. 2003 Sep 1;102(5):1634-40
references.pmid: 12750163
references.citation: Comp Biochem Physiol A Physiol. 1997 Sep;118(1):9-14
references.pmid: 9243810
references.citation: Clin Exp Pharmacol Physiol. 2006 Oct;33(10):961-7
references.pmid: 17002675
references.citation: Nature. 1975 Aug 21;256(5519):665-7
references.pmid: 1153002
references.citation: Biotechniques. 2006 Jul;41(1):59-63
references.pmid: 16869514
references.citation: Cell Metab. 2006 Mar;3(3):187-97
references.pmid: 16517406
references.citation: Physiol Rev. 1996 Jul;76(3):839-85
references.pmid: 8757790
references.citation: Cancer Sci. 2009 May;100(5):821-7
references.pmid: 19445015
references.citation: Cell. 1991 Feb 22;64(4):693-702
references.pmid: 1997203
references.citation: Biochim Biophys Acta. 2001 May 31;1532(1-2):79-87
references.pmid: 11420176
references.citation: Cancer Res. 2012 Aug 1;72(15):3709-14
references.pmid: 22787121
references.citation: J Biol Chem. 2000 Aug 25;275(34):26458-66
references.pmid: 10843999
references.citation: Cancer Res. 2006 Jun 15;66(12):6264-70
references.pmid: 16778202
references.citation: Science. 2009 May 22;324(5930):1076-80
references.pmid: 19461003
references.citation: Blood. 1973 Jul;42(1):89-98
references.pmid: 4577713
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1218-26
references.pmid: 17344427
references.citation: FASEB J. 2004 Sep;18(12):1462-4
references.pmid: 15240563
references.citation: J Biol Chem. 2011 Apr 22;286(16):13869-78
references.pmid: 21345792
references.citation: PLoS One. 2010 Jun 24;5(6):e11303
references.pmid: 20585586
references.citation: Kidney Int. 1996 Sep;50(3):937-43
references.pmid: 8872969
references.citation: Mol Cell Biol. 2006 Jul;26(14):5336-47
references.pmid: 16809770
references.citation: Mol Cell. 2013 Jan 24;49(2):310-21
references.pmid: 23201122
references.citation: Science. 2009 Jun 5;324(5932):1289-93
references.pmid: 19498162
references.citation: Cell Metab. 2006 Mar;3(3):177-85
references.pmid: 16517405
references.citation: Cancer Res. 2003 Oct 1;63(19):6130-4
references.pmid: 14559790
references.citation: J Biol Chem. 2006 Aug 11;281(32):22575-85
references.pmid: 16760477
references.citation: Eur J Biochem. 1978 Aug 15;89(1):19-22
references.pmid: 699906
references.citation: Genetics. 1949 Nov;34(6):708-23
references.pmid: 15393917
references.citation: Kidney Int. 2010 Dec;78(11):1136-53
references.pmid: 20736988
references.citation: Genes Dev. 1997 Jan 1;11(1):72-82
references.pmid: 9000051
references.citation: Biochem J. 1990 Aug 15;270(1):219-25
references.pmid: 2396982
references.citation: Pharmacotherapy. 2008 Nov;28(11):1383-90
references.pmid: 18956998
references.citation: Br Med J (Clin Res Ed). 1983 Jul 30;287(6388):308-9
references.pmid: 6409285
references.citation: Nephron Extra. 2012 Sep 27;2(1):256-68
references.pmid: 23599704
references.citation: J Biol Chem. 2001 Apr 6;276(14):11420-6
references.pmid: 11150295
references.citation: Psychol Bull. 1992 Jul;112(1):155-9
references.pmid: 19565683