GW501516 is a synthetic PPARδ-specific agonist, with an EC50 of 0.10nM [1]. Activation of PPARβ/δ by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, β-oxidation, cholesterol efflux, and energy uncoupling[2]. GW501516 can regulate the plasma lipid metabolism in animals and has been widely used as a model compound for the development of a series of new derivatives[3].
In vitro, GW501516 treatment at a concentration of 2500nM for 72 hours significantly inhibited cell proliferation and colony formation of C666-1 cells, resulting in impaired cell cycle progression[4]. The pretreatment of human pulmonary artery smooth muscle cells with GW501516 (3000nM) for 6 hours could significantly inhibit the cell migration and collagen synthesis induced by Platelet-derived growth factor (PDGF) (10ng/mL; 24 hours) [5]. GW501516 treatment (100nM) for 24 hours induced the release of growth factor in human vascular endothelial cells, as well as the expression of adipocyte differentiation-related protein (ADRP), stimulating cell proliferation and morphogenesis[6].
In vivo, GW501516 treatment (10μg/kg/day; p.o.) for 6 weeks increased liver fibrosis induced by CCl4 in mice, and increased the expression of pro-inflammatory markers and the infiltration of macrophages in the liver[7]. Intraperitoneal injection of GW501516 (2mg/kg) 6 hours before lipopolysaccharide (LPS) administration can reduce the mortality rate and liver damage in mice with acute liver failure, and lower the levels of pro-inflammatory cytokines in the serum[8].
References:
[1] Wei Z L, Kozikowski A P. A short and efficient synthesis of the pharmacological research tool GW501516 for the peroxisome proliferator-activated receptor δ[J]. The Journal of organic chemistry, 2003, 68(23): 9116-9118.
[2] Dressel U, Allen T L, Pippal J B, et al. The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells[J]. Molecular endocrinology, 2003, 17(12): 2477-2493.
[3] Ciocoiu C C, Ravna A W, Sylte I, et al. Synthesis, biological evaluation and molecular modeling of GW 501516 analogues[J]. Archiv der Pharmazie, 2010, 343(11‐12): 612-624.
[4] Ji Y, Li H, Wang F, et al. PPARβ/δ agonist GW501516 inhibits tumorigenicity of undifferentiated nasopharyngeal carcinoma in C666-1 cells by promoting apoptosis[J]. Frontiers in pharmacology, 2018, 9: 648.
[5] Liu G, Li X, Li Y, et al. PPARδ agonist GW501516 inhibits PDGF‐stimulated pulmonary arterial smooth muscle cell function related to pathological vascular remodeling[J]. BioMed research international, 2013, 2013(1): 903947.
[6] Piqueras L, Reynolds A R, Hodivala-Dilke K M, et al. Activation of PPARβ/δ induces endothelial cell proliferation and angiogenesis[J]. Arteriosclerosis, thrombosis, and vascular biology, 2007, 27(1): 63-69.
[7] Kostadinova R, Montagner A, Gouranton E, et al. GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation[J]. Cell & bioscience, 2012, 2(1): 34.
[8] Lim H J, Kwak H J. Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators[J]. Molecules, 2024, 29(21): 5189.
GW501516是一种合成PPARδ特异性激动剂，EC50值为0.10nM[1]。GW501516通过激活骨骼肌细胞中的PPARβ/δ，可诱导脂质优先利用、β-氧化、胆固醇外流和能量解偶联相关基因的表达[2]。GW501516能调节动物血浆脂质代谢，已被广泛用作开发一系列新型衍生物的模型化合物[3]。
在体外，2500nM浓度的GW501516处理72小时可显著抑制C666-1细胞增殖和克隆形成，并阻碍细胞周期进程[4]。3000nM浓度的GW501516预处理人肺动脉平滑肌细胞6小时，能显著抑制血小板衍生生长因子（PDGF）（10ng/mL；24小时）诱导的细胞迁移和胶原合成[5]。100nM浓度的GW501516处理24小时可诱导人血管内皮细胞释放生长因子，并促进脂滴包被蛋白（ADRP）表达，刺激细胞增殖和形态发生[6]。
在体内，以10μg/kg/day剂量的GW501516口服给药6周，会加剧四氯化碳（CCl4）诱导的小鼠肝纤维化，并促进肝脏炎症标志物表达及巨噬细胞浸润[7]。在脂多糖（LPS）给药前6小时腹腔注射2mg/kg剂量的GW501516，可降低急性肝衰竭小鼠的死亡率及肝损伤程度，并降低血清促炎细胞因子水平[8]。