Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction. (1st March 2017)

• Record Type: Journal Article
• Authors: Vispute, Saurabh G.; Bu, Pengli; Le, Yuan; Cheng, Xingguo
• Is Part Of: Toxicology. Volume 378(2017)
• Page Start: 95
• Page End: 106
• Publication Date: 2017-03-01
• Subjects: APAP acetaminophen -- bp base pair -- ChIP chromatin immunoprecipitation -- Cyp cytochrome p450 enzyme -- DEX dexamethasone -- Fgf21 fibroblast growth factor 21 -- GR glucocorticoid receptor -- GRE glucocorticoid receptor response element -- GSH Glutathione -- i.p. intraperitoneal -- NAPQI N-acetyl-p-benzoquinone imine -- PGC1α peroxisome proliferator-activated receptor gamma coactivator protein-1α -- PPAR peroxisome proliferator-activated receptor -- PXR pregnane X receptor -- TSS transcription start site -- WAT white adipose tissue -- WT wild-type; Fgf21 -- Dexamethasone -- Glucocorticoid receptor -- Acetaminophen -- Hepatotoxicity; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.01.009
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: DEX induced Fgf21/FGF21 expression in both mouse and human liver/hepatoma cells. Fgf21 is a direct target gene of GR. Pretreatment of 2 mg/kg DEX attenuates acetaminophen hepatotoxicity. Abstract: Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity. Our results showed that DEX dose/concentration- and time-dependently increased Fgf21 mRNA and protein expression in mouse liver as well as cultured mouse and human hepatoma cells. By using PXR-null mouse model, we demonstrated that DEX induced Fgf21 expression by a PXR-independent mechanism. In cultured mouse and human hepatoma cells, inhibition of GR signaling, by RU486 (Mifepristone) or GR silencing using GR-specific siRNA, attenuated DEX-induced Fgf21 expression. In addition, DEX increased luciferase reporter activity driven by the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Further, ChIP-qPCR assays demonstrated that DEX increased the binding of GR to the specific cis-regulatory elements located in the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Pretreatment of 2 mg/kg DEX ameliorated APAP-induced liver injury in wild-type but not Fgf21-null mice. In conclusion, via GR activation, DEX induced Fgf21 expression in mouse liver and human hepatoma cells.