Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Xingguo Cheng

Second Advisor

Blase C. Billack

Third Advisor

Zhe-Sheng Chen

Abstract

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.

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