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

BACKGROUND AND PURPOSE

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.

EXPERIMENTAL APPROACH

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.

KEY RESULTS

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.

CONCLUSIONS AND IMPLICATIONS

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.