title: Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: knockdown of SCOT inhibits insulin release in rat insulinoma cells.
abstract: Succinyl-CoA:3-ketoacid-CoA transferase (SCOT) is a mitochondrial enzyme that catalyzes the reversible transfer of coenzyme-A from acetoacetyl-CoA to succinate to form acetoacetate and succinyl-CoA. mRNAs of SCOT and ATP citrate lyase were decreased 55% and 58% and enzyme activities were decreased >70% in pancreatic islets of the GK rat, a model of type 2 diabetes. INS-1 832/13 cells were transfected with shRNAs targeting SCOT mRNA to generate cell lines with reduced SCOT activity. Two cell lines with >70% knockdown of SCOT activity showed >70% reduction in glucose- or methyl succinate-plus-beta-hydroxybutyrate-stimulated insulin release. Less inhibition of insulin release was observed with two cell lines with less knockdown of SCOT. Previous studies showed knockdown of ATP citrate lyase in INS-1 832/13 cells does not lower insulin release. The results further support work that suggests mitochondrial pathways involving SCOT which supply acetoacetate for export to the cytosol are important for insulin secretion.
authors.affiliation: Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Noaman M
authors.initials: NM
authors.lastname: Hasan
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Longacre
authors.forename: Mohammed
authors.initials: M
authors.lastname: Seed Ahmed
authors.forename: Mindy A
authors.initials: MA
authors.lastname: Kendrick
authors.forename: Harvest
authors.initials: H
authors.lastname: Gu
authors.forename: Claes-Goran
authors.initials: CG
authors.lastname: Ostenson
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacDonald
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015256:Coenzyme A-Transferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001275:ATP Citrate (pro-S)-Lyase; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase
references.citation: Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E1-15
references.pmid: 15585595
references.citation: Arch Biochem Biophys. 1993 Sep;305(2):205-14
references.pmid: 8373157
references.citation: Am J Physiol Cell Physiol. 2008 Feb;294(2):C442-50
references.pmid: 18160486
references.citation: J Biol Chem. 2007 Jan 5;282(1):200-7
references.pmid: 17102138
references.citation: Biochim Biophys Acta. 2008 Jul-Aug;1780(7-8):966-72
references.pmid: 18439432
references.citation: J Biol Chem. 1997 Jul 25;272(30):18572-9
references.pmid: 9228023
references.citation: Diabetologia. 2008 Nov;51(11):2022-30
references.pmid: 18769905
references.citation: Diabetes. 2000 Mar;49(3):424-30
references.pmid: 10868964
references.citation: Diabetologia. 2009 Jun;52(6):1087-91
references.pmid: 19296078
references.citation: Arch Biochem Biophys. 1993 Jan;300(1):201-5
references.pmid: 8424653
references.citation: J Biol Chem. 2002 Sep 6;277(36):32892-8
references.pmid: 12093799
references.citation: J Biol Chem. 1996 Feb 2;271(5):2539-42
references.pmid: 8576218
references.citation: J Biol Chem. 2007 Dec 7;282(49):35657-65
references.pmid: 17928289
references.citation: Diabetes. 1996 Nov;45(11):1626-30
references.pmid: 8866570
references.citation: Arch Biochem Biophys. 2009 Aug 15;488(2):100-4
references.pmid: 19691144
references.citation: J Biol Chem. 2006 Aug 4;281(31):22342-22351
references.pmid: 16740637
references.citation: J Biol Chem. 2007 Oct 26;282(43):31592-600
references.pmid: 17823126
references.citation: J Biol Chem. 1981 Aug 25;256(16):8287-90
references.pmid: 6790537
references.citation: Mol Cell Biochem. 2008 Jun;313(1-2):195-202
references.pmid: 18414997
references.citation: Diabetes. 2000 May;49(5):718-26
references.pmid: 10905479
references.citation: Endocrinology. 1992 Jan;130(1):167-78
references.pmid: 1370150
references.citation: J Biol Chem. 2008 Oct 17;283(42):28048-59
references.pmid: 18697738
references.citation: J Biol Chem. 2008 Oct 24;283(43):28909-17
references.pmid: 18755687
references.citation: Diabetologia. 1994 Feb;37(2):177-81
references.pmid: 8163052
references.citation: Diabetologia. 1993 Aug;36(8):722-6
references.pmid: 8405739
references.citation: J Biol Chem. 1995 Aug 25;270(34):20051-8
references.pmid: 7650022
references.citation: Arch Biochem Biophys. 1982 Feb;213(2):643-9
references.pmid: 6462111
references.citation: Diabetes. 1991 Feb;40(2):227-32
references.pmid: 1825072
references.citation: Diabetes. 1996 Jul;45(7):886-90
references.pmid: 8666138
references.citation: J Biol Chem. 2007 Oct 19;282(42):30596-606
references.pmid: 17724028
references.citation: Diabetes. 2002 Jul;51(7):2018-24
references.pmid: 12086928
references.citation: Science. 1999 Feb 12;283(5404):981-5
references.pmid: 9974390
references.citation: J Biol Chem. 2009 Dec 18;284(51):35359-67
references.pmid: 19858194
references.citation: Metabolism. 1993 Oct;42(10):1229-31
references.pmid: 8412734
references.citation: Diabetologia. 2008 Dec;51(12):2281-9
references.pmid: 18802677