Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.
Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.
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DOI：
10.1038/srep42477
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发表时间：
2017-02-14
影响因子：
4.6
通讯作者：
Nakajima A
中科院分区：
文献类型：
--
作者：
Honda Y;Kessoku T;Ogawa Y;Tomeno W;Imajo K;Fujita K;Yoneda M;Takizawa T;Saito S;Nagashima Y;Nakajima A
过氧化物酶体增殖物激活受体α激动剂（例如，贝特类（贝特类）对人类非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎（NASH）的作用尚不清楚。Pemafibrate是一种新型的选择性过氧化物酶体增殖物激活受体α调节剂，可最大限度地发挥目前使用的贝特类药物的有益作用，减少不良反应。在一项2期研究中，pemafibrate被证明可以改善血脂异常患者的肝功能障碍。在本研究中，我们首先研究了pemafibrate对NASH啮齿动物模型的影响。在饮食诱导的啮齿动物NASH模型中评估了培马贝特与非诺贝特的疗效。Pemafibrate和非诺贝特改善了肥胖、血脂异常、肝功能障碍和NASH的病理状态。Pemafibrate改善胰岛素抵抗和增加能量消耗显着。为了研究pemafibrate的作用，我们分析了参与脂质代谢的基因表达和蛋白水平。我们还分析了解偶联蛋白3（UCP 3）的表达。Pemafibrate刺激脂质周转和上调UCP 3在肝脏中的表达。pemafibrate可显著增加酰基辅酶A氧化酶1和UCP 3蛋白水平。Pemafibrate可通过调节肝脏脂质代谢和能量代谢改善NASH的发病机制。Pemafibrate是一种很有前途的NAFLD/NASH治疗药物。
The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.