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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.AT

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24158519

Citation

Bojic, Lazar A., et al. "Peroxisome Proliferator-activated Receptor Δ Agonist GW1516 Attenuates Diet-induced Aortic Inflammation, Insulin Resistance, and Atherosclerosis in Low-density Lipoprotein Receptor Knockout Mice." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 1, 2014, pp. 52-60.
Bojic LA, Burke AC, Chhoker SS, et al. 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;34(1):52-60.
Bojic, L. A., Burke, A. C., Chhoker, S. S., Telford, D. E., Sutherland, B. G., Edwards, J. Y., Sawyez, C. G., Tirona, R. G., Yin, H., Pickering, J. G., & Huff, M. W. (2014). Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(1), 52-60. https://doi.org/10.1161/ATVBAHA.113.301830
Bojic LA, et al. 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;34(1):52-60. PubMed PMID: 24158519.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice. AU - Bojic,Lazar A, AU - Burke,Amy C, AU - Chhoker,Sanjiv S, AU - Telford,Dawn E, AU - Sutherland,Brian G, AU - Edwards,Jane Y, AU - Sawyez,Cynthia G, AU - Tirona,Rommel G, AU - Yin,Hao, AU - Pickering,J Geoffrey, AU - Huff,Murray W, Y1 - 2013/10/24/ PY - 2013/10/26/entrez PY - 2013/10/26/pubmed PY - 2014/2/19/medline KW - atherosclerosis KW - inflammation KW - insulin resistance KW - lipids SP - 52 EP - 60 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 34 IS - 1 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/24158519/Peroxisome_proliferator_activated_receptor_δ_agonist_GW1516_attenuates_diet_induced_aortic_inflammation_insulin_resistance_and_atherosclerosis_in_low_density_lipoprotein_receptor_knockout_mice_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.113.301830?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -