title: Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity.
abstract: The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr(-/-) mice. We used chromatin immunoprecipitation-based genome-wide response element analyses coupled with luciferase reporter assays to identify functional FXR response elements within promoters, introns, or intragenic regions of these genes. Consistent with the observed transcriptional changes, FXR gene dosage is positively correlated with the degree of protection from APAP-induced hepatotoxicity in vivo. Further, we demonstrate that pretreatment of wild-type mice with an FXR-specific agonist provides significant protection from APAP-induced hepatotoxicity. Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Florence Ying
authors.initials: FY
authors.lastname: Lee
authors.forename: Thomas Quad
authors.initials: TQ
authors.lastname: de Aguiar Vallim
authors.forename: Hansook Kim
authors.initials: HK
authors.lastname: Chong
authors.forename: Yanqiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Jones
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000082:Acetaminophen; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated