A selective peroxisome proliferator-activated receptor δ agonist PYPEP suppresses atherosclerosis in association with improvement of the serum lipoprotein profiles in human apolipoprotein B100 and cholesteryl ester transfer protein double transgenic mice

Naya, Noriyuki; Fukao, Keita; Nakamura, Akemi; Hamada, Toshihiro; Sugimoto, Masayuki; Kojima, Masashi; Yoshimura, Norito; Uwabe, Ken‐Ichiro; Imagawa, Keiichi; Nomura, Kohji; Hara, Shinji; Nakano, Toru; Iwasaki, Takanori; Shinosaki, Toshihiro; Hanasaki, Kohji

doi:10.1016/j.metabol.2015.09.016

Cited by 10 publications

(9 citation statements)

References 37 publications

(33 reference statements)

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“…Importantly, GW501516 induced an increase in HDLc and triglyceride (TG) clearance after fat-feeding in human subjects, consistent with results in in vitro human skeletal muscle cells that GW501516 treatment upregulated fat utilization and ABCA1 expression [40]. Most recently, a novel PPARδ agonist, PYPEP, has been found to suppress atherosclerotic lesion progression by increasing serum levels of ApoA-I and HDL cholesterol, as well as reducing non-HDL cholesterol levels in hApoB100/hCETP-dTg mice with human-like hypercholesterolemic dyslipidemia [31]. These studies all suggest that PPARδ activation could modulate metabolism of lipids and be a novel, powerful treatment for patients with cardiovascular diseases [23,43].…”

Section: Introductionsupporting

confidence: 72%

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

Dong-Sheng

Hua

et al. 2016

Inflammation

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which mediate glucose and lipid homeostasis by regulating the expression of a large number of transcription factors. Sphingomyelin synthase (SMS) is a key enzyme in the synthesis of sphingomyelin (SM), and its expression and activity have been reported to be associated with atherosclerosis (AS). Although there have been many functional PPAR and SMS studies on atherosclerosis in recent years, few have investigated the correlation between the activation of PPARδ and the activity of SMS. In his study, macrophage-induced foam cells were utilized to model important pathological changes that occur in AS. The influence of PPARδ agonism by GW501516 on SMS and its product molecule SM were measured. Results indicated that the activation of PPARδ was correlated in a positive manner with the activity of SMS2, and the content of SM was dose dependently increased by GW501516. Together, this study represents the first to suggest that PPARδ activation may be a potential risk of AS through enhancing activity of SMS2.

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Section: Introductionsupporting

confidence: 72%

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

Dong-Sheng

Hua

et al. 2016

Inflammation

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“…A PPARd agonist PYPEP did not affect CEC but increased smaller HDL particles in hApoB100/hCETPdouble transgenic mice. 50 Another PPARd agonist GW0742 also did not affect HDL cholesteryl ester production, its catabolism, or total CEC but increased ABCA1mediated efflux in C57BL/6 mice. 51 Interestingly, GW0742 treatment in C57BL/6 mice resulted in increased phospholipid transfer protein expression and its activity and promoted serum potential for preb HDL formation, suggesting enhancement of macrophage cholesterol efflux.…”

Section: Discussionmentioning

confidence: 97%

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Yamashita

Arai

Yokote

et al. 2018

Journal of Clinical Lipidology

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“…Several PPAR-δ agonists are in clinical development. For example, the novel PPAR-δ agonist PYPEP improved lipids, lowered chemokine (C-C motif) ligand 2 (CCL2) and suppressed atherosclerotic lesion progression in mice 38 . CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a cytokine secreted by macrophages, adipocytes, and many other cell types that recruits inflammatory cells to sites of tissue injury or inflammation.…”

Section: Macrophage Functions In Lean Tissuementioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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A selective peroxisome proliferator-activated receptor δ agonist PYPEP suppresses atherosclerosis in association with improvement of the serum lipoprotein profiles in human apolipoprotein B100 and cholesteryl ester transfer protein double transgenic mice

Cited by 10 publications

References 37 publications

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Macrophage functions in lean and obese adipose tissue

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