Background
Pemafibrate (K-877) is an oral peroxisome proliferator-activated receptor (PPAR)-α agonist for the treatment of hyperlipidaemia, EC50 on Gal4hPPARα = 1 nM [1].
Pemafibrate (10 μM, 24 h) regulated the expression of several target genes that code for proteins involved in carbohydrate and lipid metabolism, in primary human hepatocytes and the mouse liver [2]. Pemafibrate (50 nM, 24h) activated PPAR-α transcription activity and more effectively than fenofibrate and pirinixic acid (Wy14643) [3].
Pemafibrate (0.001% in MF diets for 1 week) significantly reduced plasma triglyceride and total cholesterol levels, increased plasma HDL cholesterol levels, regulated gene expression related to triglyceride and HDL cholesterol metabolism in the liver, and regulated cholesterol and triglyceride metabolic gene expression in the small intestine in mice [4]. Pemafibrate also promoted cholesterol efflux and reverse cholesterol transport, exerted anti-inflammatory activity, and decreased atherosclerotic lesions [1]. Pemafibrate was more effective than fenofibrate at suppressing the postprandial increase of chylomicrons and the accumulation of chylomicron remnants, thereby attenuating postprandial hypertriglyceridaemia [5].
参考文献:
[1]. Hennuyer N, Duplan I, Paquet C, et al. The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis[J]. Atherosclerosis, 2016, 249: 200-208.
[2]. Raza-Iqbal S, Tanaka T, Anai M, et al. Transcriptome analysis of K-877 (a novel selective PPARα modulator (SPPARMα))-regulated genes in primary human hepatocytes and the mouse liver[J]. Journal of atherosclerosis and thrombosis, 2015: 28720.
[3]. Takei K, Han S, Murayama Y, et al. Selective peroxisome proliferator‐activated receptor‐α modulator K‐877 efficiently activates the peroxisome proliferator‐activated receptor‐α pathway and improves lipid metabolism in mice[J]. Journal of Diabetes Investigation, 2017, 8(4): 446-452.
[4]. Takei K, Nakagawa Y, Wang Y, et al. Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice[J]. Journal of pharmacological sciences, 2017, 133(4): 214-222.
[5]. Sairyo M, Kobayashi T, Masuda D, et al. A novel selective PPARα modulator (SPPARMα), K-877 (pemafibrate), attenuates postprandial hypertriglyceridemia in mice[J]. Journal of atherosclerosis and thrombosis, 2018, 25(2): 142-152.
Pemafibrate (K-877) 是一种口服过氧化物酶体增殖物激活受体 (PPAR)-α 激动剂，用于治疗高脂血症，对 Gal4hPPARα 的 EC50 = 1 nM [1]。
Pemafibrate（10 μM，24 小时）调节原代人肝细胞和小鼠肝脏中多个靶基因的表达，这些靶基因编码参与碳水化合物和脂质代谢的蛋白质[2]。 Pemafibrate (50 nM, 24h) 激活 PPAR-α 转录活性，并且比非诺贝特和 pirinixic acid (Wy14643) 更有效[3]。
Pemafibrate（0.001% MF 饮食 1 周）显着降低血浆甘油三酯和总胆固醇水平，增加血浆 HDL 胆固醇水平，调节肝脏中与甘油三酯和 HDL 胆固醇代谢相关的基因表达，并调节胆固醇和甘油三酯代谢基因在小鼠小肠中的表达[4]。 Pemafibrate 还促进胆固醇流出和逆转胆固醇转运，发挥抗炎活性，减少动脉粥样硬化病变[1]。培马贝特比非诺贝特更有效地抑制餐后乳糜微粒的增加和乳糜微粒残留物的积累，从而减轻餐后高甘油三酯血症[5]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Cryopreserved primary human hepatocytes
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Preparation Method
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The hepatocyte cultures were maintained at 37⊿ 95% humidity and 5% CO2 for 3 hours and gently replaced with InVitroGRO CP with antibiotics. After 24 hours, the hepatocytes were treated with InVitroGRO CP with antibiotics containing 100 nM and 10 μM of Pemafibrate or 0.01% DMSO as a control.
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Reaction Conditions
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100 nM and 10 μM for 24 hours
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Applications
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Pemafibrate treated 11 of the top 20 upregulated genes were involved in carbohydrate and lipid metabolism.
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| Animal experiment [2]: |
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Animal models
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Female homozygous human apoE2KI mice
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Preparation Method
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Mice were fed a western diet containing (wt/wt) 0.2% cholesterol and 21% fat for 9 weeks and treated for the last 2 weeks with fenofibrate (250 mg/kg) or pemafibrate (0.1 or 1 mg/kg) or carboxy methyl cellulose (CMC, control).
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Dosage form
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250mg/kg, 2 weeks, feed with diet.
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Applications
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Pemafibrate strongly induced ABCA1 (+563%, p < 0.01 at 10 μM) and ABCG1 (+2093% p < 0.001 at 10 μM) mRNA steady-state levels in a dose-dependent manner (+168%, p < 0.05 for ABCA1 and +506%, p < 0.01 for ABCG1)
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参考文献:
[1]: Raza-Iqbal S, Tanaka T, Anai M, et al. Transcriptome analysis of K-877 (a novel selective PPARα modulator (SPPARMα))-regulated genes in primary human hepatocytes and the mouse liver[J]. Journal of atherosclerosis and thrombosis, 2015: 28720.
[2]: Hennuyer N, Duplan I, Paquet C, et al. The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis[J]. Atherosclerosis, 2016, 249: 200-208.
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