Journal Article10.1097/MOL.0B013E32835CC949
Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player.
Lazar A. Bojic,Murray W. Huff +1 more
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TL;DR: Progresses in the understanding of PPAR&dgr; reveal that activation of this receptor represents a multifaceted therapeutic strategy for the prevention and treatment of insulin-resistant syndromes and atherosclerosis.
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Abstract: Purpose of review Therapeutic strategies to alleviate the growing epidemic of insulin-resistant syndromes (obesity and type 2 diabetes) as well as the conferred cardiovascular disease risk remain sparse The peroxisome proliferator-activated receptor δ (PPARδ) has emerged as a versatile regulator of lipid homeostasis and inflammatory signaling, making it an attractive therapeutic target for the treatment and prevention of type 2 diabetes and atherosclerosis Recent findings PPARδ activation regulates lipid homeostasis and inflammatory signaling in a variety of cell types, conferring protection from metabolic disease and atherosclerosis Specifically, PPARδ activation in the liver stimulates glucose utilization and inhibits gluconeogenesis, which improves insulin resistance and hyperglycemia In macrophages, PPARδ-specific activation with synthetic agonists inhibits VLDL-induced triglyceride accumulation and inflammation In mice, PPARδ agonists halt the progression of atherosclerosis and stabilize existing lesions by promoting an anti-inflammatory milieu within the diseased macrovasculature In humans, PPARδ activation improves insulin sensitivity and reduces atherogenic dyslipidemia via a mechanism complementary to statin monotherapy Summary Recent advances in the understanding of PPARδ reveal that activation of this receptor represents a multifaceted therapeutic strategy for the prevention and treatment of insulin-resistant syndromes and atherosclerosis
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References
Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein
Lazar A. Bojic,Cynthia G. Sawyez,Dawn E. Telford,Jane Y. Edwards,Robert A. Hegele,Murray W. Huff +5 more
TL;DR: The combined PPAR&dgr;-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.
50
Modification of type III VLDL, their remnants, and VLDL from apoE- knockout mice by p-hydroxyphenylacetaldehyde, a product of myeloperoxidase activity, causes marked cholesteryl ester accumulation in macrophages
Stewart C. Whitman,Stanley L. Hazen,David B. Miller,Robert A. Hegele,Jay W. Heinecke,Murray W. Huff +5 more
TL;DR: A novel mechanism for the conversion of type III VLDLs, their remnants, and EKO-VLDL into atherogenic particles is demonstrated and it is suggested that macrophage uptake of pHA-V LDL requires catalytically active lipoprotein lipase and involves pathways distinct from the SR-A.
28
Uptake of type IV hypertriglyceridemic VLDL by cultured macrophages is enhanced by interferon-gamma.
Stewart C. Whitman,Carmen Argmann,Cynthia G. Sawyez,David B. Miller,Robert A. Hegele,Murray W. Huff +5 more
TL;DR: IFN-gamma may promote foam cell formation by accelerating macrophage uptake of native lipoproteins through mediated by the LDL-receptor and requires ACAT-mediated cholesterol esterification.
21
The Role of Endoplasmic Reticulum Stress in the Progression of Atherosclerosis
TL;DR: Although exciting work over the last decade has begun to shed light on the mechanisms and in vivo relevance of ER stress-driven atherosclerosis, much more work is needed to fully understand and enable an informed approach to therapeutic translation.
Transcriptional Repression of Atherogenic Inflammation: Modulation by PPARδ
TL;DR: An unconventional ligand-dependent transcriptional pathway is proposed in which PPARδ controls an inflammatory switch through its association and disassociation with transcriptional repressors and may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.
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