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

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Manyun Dai1, Julin Yang2, Minzhu Xie1

  • 1Medical School of Ningbo University, Ningbo, China.

British Journal of Pharmacology
|June 25, 2017
PubMed
Abstract

Insights

Fenofibrate protects against cholestasis-induced liver injury by activating PPARα and inhibiting JNK signaling. This mechanism offers potential new therapies for cholestatic liver diseases.

Area of Science:

  • Hepatology and Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Fenofibrate, a PPARα agonist, is widely used for hyperlipidemia.
  • Fibrates show promise for cholestasis, but mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanism of fenofibrate's protective effects in cholestasis.
  • To investigate the roles of PPARα and JNK signaling pathways.

Main Methods:

  • Used wild-type and Pparα-null mice with ANIT-induced cholestasis.
  • Administered fenofibrate, WY14643 (PPARα agonist), and SP600125 (JNK inhibitor).
  • Evaluated fenofibrate in a DDC-induced sclerosing cholangitis model.

Main Results:

  • Fenofibrate (25 mg·kg⁻¹ BID) protected against ANIT-induced cholestasis and liver injury in wild-type but not Pparα-null mice.
  • PPARα activation and JNK inhibition correlated with protection.
  • Fenofibrate showed benefits in a sclerosing cholangitis model.

Conclusions:

  • Fenofibrate's protection against cholestatic liver injury is PPARα-dependent and dose-related.
  • The mechanism involves JNK signaling inhibition.
  • Fenofibrate offers therapeutic potential for intrahepatic cholestasis.

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