title: SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation.
abstract: Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.
authors.affiliation: Department of Cell Biology, The Paul F. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Laurent
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.forename: Meredith
authors.initials: M
authors.lastname: Sweeney
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Thaddeus T
authors.initials: TT
authors.lastname: Schug
authors.forename: Yana
authors.initials: Y
authors.lastname: Cen
authors.forename: Seung Min
authors.initials: SM
authors.lastname: Jeong
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005215:Fasting; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D005227:Fatty Acids; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D009243:NAD; C514813:SIRT4 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins
references.citation: AAPS J. 2006 Oct 06;8(4):E632-43
references.pmid: 17233528
references.citation: Mol Biol Cell. 2005 Oct;16(10):4623-35
references.pmid: 16079181
references.citation: Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8
references.pmid: 10873683
references.citation: Nature. 2000 Feb 17;403(6771):795-800
references.pmid: 10693811
references.citation: PLoS Genet. 2008 Aug 15;4(8):e1000161
references.pmid: 18704162
references.citation: J Clin Invest. 1999 Jun;103(11):1489-98
references.pmid: 10359558
references.citation: Genome Biol. 2001;2(8):RESEARCH0032
references.pmid: 11532216
references.citation: J Cell Biol. 2002 Aug 19;158(4):647-57
references.pmid: 12186850
references.citation: J Clin Invest. 2006 Mar;116(3):571-80
references.pmid: 16511589
references.citation: Physiol Rev. 2006 Apr;86(2):465-514
references.pmid: 16601267
references.citation: Cell Metab. 2009 Apr;9(4):327-38
references.pmid: 19356714
references.citation: Cell Mol Life Sci. 2004 Feb;61(4):393-416
references.pmid: 14999402
references.citation: Nature. 2006 Dec 14;444(7121):868-74
references.pmid: 17167475
references.citation: J Biol Chem. 2010 Oct 15;285(42):31995-2002
references.pmid: 20685656
references.citation: EMBO J. 1992 Feb;11(2):433-9
references.pmid: 1537328
references.citation: BMC Genomics. 2007 May 22;8:125
references.pmid: 17519032
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6658-63
references.pmid: 10841563
references.citation: Aging Cell. 2004 Oct;3(5):283-96
references.pmid: 15379852
references.citation: Cell. 1992 Mar 6;68(5):879-87
references.pmid: 1312391
references.citation: Age (Dordr). 2006 Jun;28(2):125-44
references.pmid: 19943135
references.citation: Pathol Res Pract. 1980;167(2-4):217-33
references.pmid: 7433233
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7473-8
references.pmid: 10377439
references.citation: Heredity (Edinb). 2007 Aug;99(2):143-50
references.pmid: 17473866
references.citation: Science. 2009 May 1;324(5927):651-4
references.pmid: 19299583
references.citation: Endocr Rev. 2010 Apr;31(2):194-223
references.pmid: 20007326
references.citation: PLoS Biol. 2005 Apr;3(4):e101
references.pmid: 15760270
references.citation: Cell. 2004 Oct 1;119(1):121-35
references.pmid: 15454086
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14178-82
references.pmid: 11106374
references.citation: Biochim Biophys Acta. 2010 Aug;1804(8):1584-90
references.pmid: 19897060
references.citation: EMBO J. 2007 Apr 4;26(7):1913-23
references.pmid: 17347648
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):415-20
references.pmid: 11134535
references.citation: PPAR Res. 2007;2007:26839
references.pmid: 18288265
references.citation: Mol Cell Biol. 2006 Jan;26(1):28-38
references.pmid: 16354677
references.citation: Nature. 2005 Mar 3;434(7029):113-8
references.pmid: 15744310
references.citation: BMC Bioinformatics. 2005 Nov 09;6:269
references.pmid: 16280084
references.citation: J Biol Chem. 1998 Sep 11;273(37):23786-92
references.pmid: 9726988
references.citation: Physiol Genomics. 2005 Nov 17;23(3):343-50
references.pmid: 16189280
references.citation: Cell. 2006 Sep 8;126(5):941-54
references.pmid: 16959573
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11
references.pmid: 10811920
references.citation: Mol Cell. 2013 Jun 6;50(5):686-98
references.pmid: 23746352
references.citation: Cell Metab. 2006 Dec;4(6):453-64
references.pmid: 17141629
references.citation: Ageing Res Rev. 2009 Jul;8(3):173-88
references.pmid: 19491041