title: Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice.
abstract: OBJECTIVE
  The peroxisome proliferator-activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis.
  
  
  RESULTS
  Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene Adfp but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis.
authors.affiliation: From the Department of Vascular Biology, Robarts Research Institute (L.A.B., A.C.B., S.S.C., D.E.T., B.G.S., J.Y.E., C.G.S., H.Y., J.G.P., M.W.H.), London, Ontario, Canada; and Departments of Biochemistry (L.A.B., A.C.B., S.S.C., J.G.P., M.W.H.), Medicine (D.E.T., J.Y.E., C.G.S., R.G.T., J.G.P., M.W.H.), and Physiology and Pharmacology (R.G.T.), The University of Western Ontario, London, Ontario, Canada.
authors.forename: Lazar A
authors.initials: LA
authors.lastname: Bojic
authors.forename: Amy C
authors.initials: AC
authors.lastname: Burke
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Chhoker
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: Brian G
authors.initials: BG
authors.lastname: Sutherland
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001025:Aortitis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002791:Cholesterol, Dietary; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001786:Blood Glucose; D002791:Cholesterol, Dietary; C425931:GW 501516; D018836:Inflammation Mediators; D007328:Insulin; D008055:Lipids; D047494:PPAR delta; D011973:Receptors, LDL; D013844:Thiazoles
keywords: atherosclerosis; inflammation; insulin resistance; lipids