Activation of activator protein-1-fibroblast growth factor 21 signaling attenuates Cisplatin hepatotoxicity

Abstract

Fibroblast growth factor (Fgf/FGF) 21, which plays important roles in sugar, lipid and energy metabolism, has been accepted as a mito-stress marker gene. We recently reported that FGF21 expression can be up-regulated via activation of aryl hydrocarbon receptor (AhR) or glucocorticoid receptor (GR) and that FGF21 plays important cytoprotective roles. Cisplatin (cis-diamminedichloroplatinum, CDDP) is a widely used chemotherapeutic drug. Numerous adverse effects including hepatotoxicity have been noted during CDDP therapy. It is known that CDDP can induce mitochondrial dysfunction. The studies were designed to determine the regulation of Fgf/FGF21 expression by CDDP, and to characterize the underlying mechanisms of its regulation, as well as to determine the impact of gain or loss of Fgf/FGF21 function on the progression of CDDP hepatotoxicity. Our results showed that CDDP and phorbol ester induced mRNA and protein expression of Fgf/FGF21 and β-Klotho, two essential components of Fgf21 signaling, in mouse livers and cultured mouse/human hepatocytes. Luciferase reporter assays and ChIP-qPCR assays demonstrated that the cJun-AP-1 activation is responsible for CDDP- and phorbol ester-induced Fgf/FGF21 expression. Such induction is abolished after cotreated with AP-1 inhibitor SR11302. In addition, CDDP produces more severe liver injury in Fgf21-null than wild-type mice. Pre-treatment of GR activator dexamethasone or AhR activator β-Naphthoflavone, both of which can induce Fgf21 expression, attenuated CDDP-induced hepatotoxicity in vivo and in vitro. In conclusion, Fgf/FGF21-β-Klotho signaling can be activated via AP-1 activation. Gain of Fgf/FGF21 function attenuates the progression of CDDP hepatotoxicity, which may be considered clinically to improve CDDP therapy.