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.

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.

• Authors: Lazar A Bojic, Amy C Burke, Sanjiv S Chhoker, Dawn E Telford, Brian G Sutherland, Jane Y Edwards, Cynthia G Sawyez, Rommel G Tirona, Hao Yin, J Geoffrey Pickering, Murray W Huff
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 1 Pg. 52-60 (Jan 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24158519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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