title: Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis.
abstract: BACKGROUND
  Stearoyl-coenzyme A desaturase 1 (SCD1) is a well-known enhancer of the metabolic syndrome. The purpose of the present study was to investigate the role of SCD1 in lipoprotein metabolism and atherosclerosis progression.
  
  
  RESULTS
  Antisense oligonucleotides were used to inhibit SCD1 in a mouse model of hyperlipidemia and atherosclerosis (LDLr(-/-)Apob(100/100)). In agreement with previous reports, inhibition of SCD1 protected against diet-induced obesity, insulin resistance, and hepatic steatosis. Unexpectedly, however, SCD1 inhibition strongly promoted aortic atherosclerosis, which could not be reversed by dietary oleate. Further analyses revealed that SCD1 inhibition promoted accumulation of saturated fatty acids in plasma and tissues and reduced plasma triglyceride, yet had little impact on low-density lipoprotein cholesterol. Because dietary saturated fatty acids have been shown to promote inflammation through toll-like receptor 4, we examined macrophage toll-like receptor 4 function. Interestingly, SCD1 inhibition resulted in alterations in macrophage membrane lipid composition and marked hypersensitivity to toll-like receptor 4 agonists.
  
  
  CONCLUSIONS
  This study demonstrates that atherosclerosis can occur independently of obesity and insulin resistance and argues against SCD1 inhibition as a safe therapeutic target for the metabolic syndrome.
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine, Section on Lipid Sciences, Winston-Salem, NC 27157-1040, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.forename: Soonkyu
authors.initials: S
authors.lastname: Chung
authors.forename: Janet K
authors.initials: JK
authors.lastname: Sawyer
authors.forename: Chiara
authors.initials: C
authors.lastname: Degirolamo
authors.forename: Heather M
authors.initials: HM
authors.lastname: Alger
authors.forename: Tam
authors.initials: T
authors.lastname: Nguyen
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.forename: My-Ngan
authors.initials: MN
authors.lastname: Duong
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Wibley
authors.forename: Ramesh
authors.initials: R
authors.lastname: Shah
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Davis
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kelley
authors.forename: Martha D
authors.initials: MD
authors.lastname: Wilson
authors.forename: Carol
authors.initials: C
authors.lastname: Kent
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
references.citation: J Lipid Res. 2004 Sep;45(9):1674-82
references.pmid: 15210843
references.citation: J Clin Invest. 2006 Nov;116(11):3015-25
references.pmid: 17053832
references.citation: Atherosclerosis. 2003 Sep;170(1):187-90
references.pmid: 12957699
references.citation: J Clin Invest. 2006 Jun;116(6):1686-95
references.pmid: 16741579
references.citation: J Biol Chem. 2004 Aug 13;279(33):35017-24
references.pmid: 15180999
references.citation: J Lipid Res. 2008 Jan;49(1):217-29
references.pmid: 17960025
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Feb;68(2):113-21
references.pmid: 12538075
references.citation: N Engl J Med. 2002 Jul 18;347(3):185-92
references.pmid: 12124407
references.citation: Circulation. 2005 Oct 25;112(17):2735-52
references.pmid: 16157765
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1396-402
references.pmid: 17431188
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):84-91
references.pmid: 17082484
references.citation: J Biol Chem. 2004 Jun 11;279(24):25164-71
references.pmid: 15066988
references.citation: Arterioscler Thromb. 1993 Oct;13(10):1515-24
references.pmid: 8399089
references.citation: Circulation. 2007 Apr 3;115(13):1806-10; discussion 1811
references.pmid: 17404171
references.citation: Cell Metab. 2008 Feb;7(2):135-47
references.pmid: 18249173
references.citation: Circ Res. 2002 Aug 23;91(4):281-91
references.pmid: 12193460
references.citation: J Lipid Res. 2002 Nov;43(11):1899-907
references.pmid: 12401889
references.citation: Science. 2002 Jul 12;297(5579):240-3
references.pmid: 12114623
references.citation: Diabetes. 2007 May;56(5):1228-39
references.pmid: 17369521
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11482-6
references.pmid: 12177411
references.citation: Obes Rev. 2005 May;6(2):169-74
references.pmid: 15836467
references.citation: J Clin Invest. 2005 Apr;115(4):1030-8
references.pmid: 15761499
references.citation: J Clin Invest. 2000 Dec;106(12):1501-10
references.pmid: 11120757
references.citation: J Lipid Res. 2006 Dec;47(12):2668-80
references.pmid: 17005996
references.citation: J Biol Chem. 2000 Sep 29;275(39):30132-8
references.pmid: 10899171
references.citation: J Biol Chem. 2006 Oct 13;281(41):31119-30
references.pmid: 16912041
references.citation: Nat Immunol. 2005 Jun;6(6):565-70
references.pmid: 15895089
references.citation: J Biol Chem. 2007 Aug 3;282(31):22678-88
references.pmid: 17526931
references.citation: Mol Cell Biol. 2006 Sep;26(18):6786-98
references.pmid: 16943421
references.citation: J Biol Chem. 2001 May 18;276(20):16683-9
references.pmid: 11278967
references.citation: J Biol Chem. 2003 Feb 21;278(8):5813-20
references.pmid: 12482877
references.citation: J Clin Invest. 2006 Jul;116(7):1813-22
references.pmid: 16823479
references.citation: J Clin Invest. 1997 Jul 1;100(1):74-83
references.pmid: 9202059
references.citation: J Clin Invest. 2004 Feb;113(3):414-24
references.pmid: 14755338
references.citation: Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):629-36
references.pmid: 18174459
references.citation: Eur J Clin Invest. 2004 Feb;34(2):94-9
references.pmid: 14764071
references.citation: Cell Metab. 2007 Mar;5(3):167-79
references.pmid: 17339025
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: Curr Drug Targets Immune Endocr Metabol Disord. 2003 Dec;3(4):271-80
references.pmid: 14683458
references.citation: Cell Metab. 2007 Dec;6(6):484-96
references.pmid: 18054317