Peroxisome Proliferator-Activated Receptor δ Agonist GW1516 Attenuates Diet-Induced Aortic Inflammation, Insulin Resistance, and Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice

Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):52-60. doi: 10.1161/ATVBAHA.113.301830. Epub 2013 Oct 24.

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.

Approach and 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.

Keywords: atherosclerosis; inflammation; insulin resistance; lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Aortitis / blood
  • Aortitis / etiology
  • Aortitis / genetics
  • Aortitis / pathology
  • Aortitis / prevention & control*
  • Atherosclerosis / blood
  • Atherosclerosis / etiology
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Cholesterol, Dietary
  • Diet, High-Fat
  • Disease Models, Animal
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy
  • Dyslipidemias / genetics
  • Dyslipidemias / metabolism
  • Inflammation Mediators / metabolism
  • Insulin / blood
  • Insulin Resistance*
  • Lipids / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR delta / agonists*
  • PPAR delta / metabolism
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology*
  • Time Factors

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Blood Glucose
  • Cholesterol, Dietary
  • GW 501516
  • Inflammation Mediators
  • Insulin
  • Lipids
  • PPAR delta
  • Receptors, LDL
  • Thiazoles