UP-REGULATION OF FIBROBLAST GROWTH FACTOR (FGF) 21 VIA AP-1 ACTIVATION ATTENUATES CISPLATIN-INDUCED HEPATOTOXICITY
Date of Award
Blase C. Billack
Fibroblast growth factor (Fgf in rodents and FGF in human) 21 plays important roles in the maintenance of sugar, lipid and energy homeostasis. Fgf/FGF21 can be up-regulated via activation of peroxisome proliferator-activated receptors (PPARs), aryl hydrocarbon receptor (AhR), glucocorticoid receptor (GR), and activating transcription factor (ATF) 4. Recent studies also demonstrated that Fgf/FGF21 plays cytoprotective roles against chemical-induced toxicities, such as of dioxins, acetaminophen, and alcohols. Cisplatin (cis-diamminedichloroplatinum, CDDP) is a widely used chemotherapeutic drug. However, numerous adverse effects have been noted during CDDP therapy, which largely limit its clinical applications. This study was 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 significance of gain of Fgf/FGF21 function in attenuating CDDP-induced liver injury. Our results showed that CDDP induced mRNA and protein expression of Fgf/FGF21 in mouse livers as well as in cultured mouse and human hepatoma cells. In addition, CDDP activated activator protein-1 (AP)-1 but not ATF4 or Nrf2 signaling in mouse livers. We further demonstrated that the AP-1 activation is responsible for CDDP-induced Fgf/FGF21 expression. Furthermore, CDDP produces more severe liver injury and inflammation in Fgf21-null than wild-type mice. Pre-treatment of dexamethasone (DEX) or β-Naphthoflavone (BNF), which induces Fgf21 expression, attenuated CDDP-induced hepatotoxicity. In conclusion, CDDP induced Fgf/FGF21 expression in mouse liver and mouse/human hepatoma cells via AP-1 activation. In addition, gain of Fgf/FGF21 function plays protective roles against CDDP-induced hepatotoxicity.
Zhang, Yue, "UP-REGULATION OF FIBROBLAST GROWTH FACTOR (FGF) 21 VIA AP-1 ACTIVATION ATTENUATES CISPLATIN-INDUCED HEPATOTOXICITY" (2021). Theses and Dissertations. 295.