title: Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction.
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 2mg/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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Saurabh G
authors.initials: SG
authors.lastname: Vispute
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA; Department of Biological Sciences, College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Pengli
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Le
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA. Electronic address: chengx@stjohns.edu.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Cheng
mesh_terms: D000082:Acetaminophen; D000818:Animals; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; C414620:fibroblast growth factor 21; D015735:Mifepristone; D000082:Acetaminophen; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione
keywords: Acetaminophen; Dexamethasone; Fgf21; Glucocorticoid receptor; Hepatotoxicity