title: Metabolite regulation of nucleo-cytosolic trafficking of carbohydrate response element-binding protein (ChREBP): role of ketone bodies.
abstract: The carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in converting excess carbohydrate to storage fat in liver. In response to changing glucose levels, ChREBP activity is regulated by nucleo-cytoplasmic shuttling of ChREBP via interactions with 14-3-3 proteins and importins. The nuclear/cytosol trafficking is regulated partly by phosphorylation/dephosphorylation of serine 196 mediated by cAMP-dependent protein kinase and protein phosphatase. We show here that protein-free extracts of starved and high fat-fed livers contain metabolites that activate interaction of ChREBP·14-3-3 and inhibit the ChREBP/importin α interaction, resulting in cytosolic localization. These metabolites were identified as β-hydroxybutyrate and acetoacetate. Nuclear localization of GFP-ChREBP is rapidly inhibited in hepatocytes incubated in β-hydroxybutyrate or fatty acids, and the observed inhibition is closely correlated with the production of ketone bodies. These observations show that ketone bodies play an important role in the regulation of ChREBP activity by restricting ChREBP localization to the cytoplasm, thus inhibiting fat synthesis during periods of ketosis.
authors.affiliation: From the Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ge
authors.forename: Robert
authors.initials: R
authors.lastname: Pawlosky
authors.forename: R Max
authors.initials: RM
authors.lastname: Wynn
authors.forename: Richard L
authors.initials: RL
authors.lastname: Veech
authors.forename: Kosaku
authors.initials: K
authors.lastname: Uyeda
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism / Q000502:physiology*; D001692:Biological Transport; D050260:Carbohydrate Metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism*; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007657:Ketone Bodies; C442825:Mlxipl protein, rat
keywords: Acetoacetate; Carbohydrate Metabolism; Lipogenesis; Signal Transduction; Transcription Factors
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9116-21
references.pmid: 11470916
references.citation: Proc Natl Acad Sci U S A. 2004 May 11;101(19):7281-6
references.pmid: 15118080
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13710-5
references.pmid: 11698644
references.citation: J Biol Chem. 2008 Sep 5;283(36):24899-908
references.pmid: 18606808
references.citation: Biochem J. 1967 May;103(2):514-27
references.pmid: 4291787
references.citation: J Biol Chem. 2011 Aug 12;286(32):28119-27
references.pmid: 21665952
references.citation: Biochem Biophys Res Commun. 2010 May 7;395(3):395-400
references.pmid: 20382127
references.citation: J Biol Chem. 2005 Mar 25;280(12):12019-27
references.pmid: 15664996
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5107-12
references.pmid: 12684532
references.citation: Biochem J. 1984 Aug 1;221(3):665-73
references.pmid: 6089744
references.citation: Cell Metab. 2006 Aug;4(2):107-10
references.pmid: 16890538
references.citation: J Hepatol. 2012 Jan;56(1):199-209
references.pmid: 21835137
references.citation: Hum Mol Genet. 2001 Mar 15;10(6):617-27
references.pmid: 11230181
references.citation: Semin Cancer Biol. 2006 Jun;16(3):173-82
references.pmid: 16678437
references.citation: Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E358-64
references.pmid: 16705063
references.citation: J Biol Chem. 2012 Dec 7;287(50):41914-21
references.pmid: 23086940
references.citation: Hum Mol Genet. 2004 Jul 15;13(14):1505-14
references.pmid: 15163635
references.citation: Am J Physiol. 1998 Sep;275(3):E516-24
references.pmid: 9725820
references.citation: Diabetes. 2011 May;60(5):1399-413
references.pmid: 21471514
references.citation: J Biol Chem. 2002 Feb 8;277(6):3829-35
references.pmid: 11724780
references.citation: Tohoku J Exp Med. 2008 Jul;215(3):227-36
references.pmid: 18648183
references.citation: Biochem Biophys Res Commun. 2010 Nov 26;402(4):784-9
references.pmid: 21036147
references.citation: J Biol Chem. 1987 Mar 5;262(7):3165-73
references.pmid: 2950095
references.citation: J Clin Invest. 2010 Dec;120(12):4316-31
references.pmid: 21084751