title: Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis.
abstract: Acetyl-CoA carboxylase (ACC), the first committed enzyme in fatty acid (FA) synthesis, is regulated by phosphorylation/dephosphorylation, transcription, and an unusual mechanism of protein polymerization. Polymerization of ACC increases enzymatic activity and is induced in vitro by supraphysiological concentrations of citrate (> 5 mM). Here, we show that MIG12, a 22 kDa cytosolic protein of previously unknown function, binds to ACC and lowers the threshold for citrate activation into the physiological range (< 1 mM). In vitro, recombinant MIG12 induced polymerization of ACC (as determined by nondenaturing gels, FPLC, and electron microscopy) and increased ACC activity by > 50-fold in the presence of 1 mM citrate. In vivo, overexpression of MIG12 in liver induced ACC polymerization, increased FA synthesis, and produced triglyceride accumulation and fatty liver. Thus, in addition to its regulation by phosphorylation and transcription, ACC is regulated at a tertiary level by MIG12, which facilitates ACC polymerization and enhances enzymatic activity.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors.forename: Chai-Wan
authors.initials: CW
authors.lastname: Kim
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Moon
authors.forename: Sahng Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Dong
authors.initials: D
authors.lastname: Cheng
authors.forename: Hyock Joo
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D005227:Fatty Acids; D008869:Microtubule-Associated Proteins; C485294:Mig12 protein, mouse; D000103:Acetyl-CoA Carboxylase
references.citation: Proc Natl Acad Sci U S A. 1966 Jul;56(1):148-55
references.pmid: 5229843
references.citation: J Biol Chem. 1988 May 5;263(13):6447-53
references.pmid: 2896193
references.citation: Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E358-64
references.pmid: 16705063
references.citation: J Clin Invest. 1996 Oct 1;98(7):1575-84
references.pmid: 8833906
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S138-43
references.pmid: 19047759
references.citation: J Biol Chem. 1985 May 25;260(10):6318-23
references.pmid: 2860106
references.citation: J Clin Invest. 2002 May;109(9):1125-31
references.pmid: 11994399
references.citation: J Nutr. 2002 Apr;132(4):643-51
references.pmid: 11925455
references.citation: Nature. 2008 Jul 24;454(7203):470-7
references.pmid: 18650918
references.citation: J Biol Chem. 1990 Jan 25;265(3):1502-9
references.pmid: 1967254
references.citation: Protein Expr Purif. 2007 Jan;51(1):11-21
references.pmid: 16854592
references.citation: Biochim Biophys Acta. 1958 Jul;29(1):225-6
references.pmid: 13560478
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1444-9
references.pmid: 10677481
references.citation: Cell. 2009 Aug 7;138(3):476-88
references.pmid: 19646743
references.citation: J Clin Invest. 1977 Jul;60(1):265-70
references.pmid: 874089
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15597-602
references.pmid: 15496471
references.citation: J Lipid Res. 2009 Mar;50(3):412-423
references.pmid: 18838740
references.citation: BMC Cell Biol. 2004 Feb 29;5:9
references.pmid: 15070402
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):5987-92
references.pmid: 9600904
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
references.pmid: 14512514
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245-50
references.pmid: 15266058
references.citation: Endocrinology. 2005 Aug;146(8):3343-50
references.pmid: 15890771
references.citation: J Clin Invest. 2004 Apr;113(8):1168-75
references.pmid: 15085196
references.citation: J Biol Chem. 2002 Mar 29;277(13):11019-25
references.pmid: 11790787
references.citation: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5473-7
references.pmid: 2899891
references.citation: Cell Metab. 2009 Jul;10(1):9-12
references.pmid: 19583949
references.citation: Biochim Biophys Acta. 2008 Jul-Aug;1780(7-8):1004-9
references.pmid: 18505691
references.citation: Biochim Biophys Acta. 2009 Jun;1794(6):961-7
references.pmid: 19236960
references.citation: J Biol Chem. 1989 Oct 25;264(30):17631-4
references.pmid: 2572585