Inhibition of JNK signalling mediates PPAR-dependent protection against intrahepatic cholestasis by fenofibrate

Background and PurposeFenofibrate, a PPAR 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. Experimental ApproachWild-type mice and Ppar-null mice were pretreated orally with fenofibrate for 3 days, following which -naphthylisothiocyanate (ANIT) was administered to induce cholestasis. The PPAR agonist WY14643 and JNK inhibitor SP600125 were used to determine the role of PPAR 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. Key ResultsFenofibrate, 25mgkg(-1) 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 Ppar-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. Conclusions and ImplicationsThese data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPAR 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.