Dai Manyun, Yang Julin, Xie Minzhu, Lin Jiao, Luo Min, Hua Huiying, Xu Gangming, Lin Hante, Song Danjun, Cheng Yuqing, Guo Bin, Zhao Jinshun, Gonzalez Frank J, Liu Aiming
Medical School of Ningbo University, Ningbo, China.
Ningbo College of Health Sciences, Ningbo, China.
Br J Pharmacol. 2017 Sep;174(18):3000-3017. doi: 10.1111/bph.13928. Epub 2017 Aug 10.
Fenofibrate, a PPARα agonist, is the most widely prescribed drug for treating hyperlipidaemia. Although fibrate drugs are reported to be beneficial for cholestasis, their underlying mechanism has not been determined.
Wild-type mice and Pparα-null mice were pretreated orally with fenofibrate for 3 days, following which α-naphthylisothiocyanate (ANIT) was administered to induce cholestasis. The PPARα agonist WY14643 and JNK inhibitor SP600125 were used to determine the role of PPARα and the JNK pathway, respectively, in cholestatic liver injury. The same fenofibrate regimen was applied to investigate its beneficial effects on sclerosing cholangitis in a DDC-induced cholestatic model.
Fenofibrate, 25 mg·kg twice a day, totally attenuated ANIT-induced cholestasis and liver injury as indicated by biochemical and histological analyses. This protection occurred in wild-type, but not in Pparα-null, mice. Alterations in bile acid synthesis and transport were found to be an adaptive response rather than a direct effect of fenofibrate. WY14643 attenuated ANIT-induced cholestasis and liver injury coincident with inhibition of JNK signalling. Although SP600125 did not affect cholestasis, it inhibited liver injury in the ANIT model when the dose of fenofibrate used was ineffective. Fenofibrate was also revealed to have a beneficial effect in the sclerosing cholangitis model.
These data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPARα and fenofibrate dose, and are mediated through inhibition of JNK signalling. This mechanism of fenofibrate protection against intrahepatic cholestasis may offer additional therapeutic opportunities for cholestatic liver diseases.
非诺贝特是一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，是治疗高脂血症处方最广泛的药物。尽管据报道贝特类药物对胆汁淤积有益，但其潜在机制尚未明确。
野生型小鼠和Pparα基因敲除小鼠口服非诺贝特预处理3天，随后给予α-萘异硫氰酸酯（ANIT）诱导胆汁淤积。分别使用PPARα激动剂WY14643和JNK抑制剂SP600125来确定PPARα和JNK信号通路在胆汁淤积性肝损伤中的作用。采用相同的非诺贝特给药方案来研究其对二甲基二苯并噻唑（DDC）诱导的胆汁淤积模型中硬化性胆管炎的有益作用。
生化和组织学分析表明，每天两次、每次25mg·kg的非诺贝特完全减轻了ANIT诱导的胆汁淤积和肝损伤。这种保护作用在野生型小鼠中出现，但在Pparα基因敲除小鼠中未出现。胆汁酸合成和转运的改变被发现是一种适应性反应，而非非诺贝特的直接作用。WY14643减轻了ANIT诱导的胆汁淤积和肝损伤，同时抑制了JNK信号传导。尽管SP600125不影响胆汁淤积，但当所用非诺贝特剂量无效时，它在ANIT模型中抑制了肝损伤。非诺贝特在硬化性胆管炎模型中也显示出有益作用。
这些数据表明，非诺贝特对胆汁淤积性肝损伤的保护作用依赖于PPARα和非诺贝特剂量，并通过抑制JNK信号传导介导。非诺贝特预防肝内胆汁淤积的这种机制可能为胆汁淤积性肝病提供额外的治疗机会。
