Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activi
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ORIGINAL ARTICLE
Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell Dongsheng Mou,1 Hua Yang,2 Changhua Qu,2 Juan Chen,2 and Chaogui Zhang2,3
Abstract—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. KEY WORDS: peroxisome proliferator-activated receptors; GW501516; sphingomyelin synthase; atherosclerosis.
INTRODUCTION Atherosclerosis remains one of the leading causes of death every year. It is likely that multiple mechanisms contribute to the formation of atherosclerosis, such as hyperlipemia, inflammation, and immunity. Recently, the role of peroxisome proliferator-activated receptors (PPARs) and sphingomyelin synthase (SMS) have received increased attention [1, 24, 30]. PPARs are ligandactivated transcription factors, which belong to the nuclear receptor superfamily. There are three related PPAR family Dongsheng Mou and Hua Yang contributed equally to this work. 1
Hubei University for Nationalities, Enshi, Hubei 445000, China Department of Neurology, University Hospital of Hubei University for Nationalities, Enshi, Hubei 445000, China 3 To whom correspondence should be addressed at Department of Neurology, University Hospital of Hubei University for Nationalities, Enshi, Hubei 445000, China. E-mail: [email protected] 2
members, PPARα, PPARγ, and PPARδ. Emerging evidence indicates that PPARα and PPARγ are involved in regulating lipid metabolism and adipocyte differentiation, which are associated with a number of metabolic disorders in the clinic such as diabetes, obesity, and atherosclerosis [22, 29, 36, 39]. PPARδ is ubiquitously expressed including brain, adipose tissue, heart, and skeletal muscles [37]. However, some physiological functions of PPARδ remain to be elucidated. PPARδ plays an important role in controlling glucose and lipid homeostasis by regulating the expression of a large number of genes [20]. Many recent studies provided evidence which support its role in
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