title: Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.
abstract: The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Edwina S
authors.initials: ES
authors.lastname: Baskin-Bey
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishimura
authors.forename: Hajime
authors.initials: H
authors.lastname: Isomoto
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.forename: Karen
authors.initials: K
authors.lastname: Braley
authors.forename: Ruth W
authors.initials: RW
authors.lastname: Craig
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A / Q000633:toxicity; D000090702:Constitutive Androstane Receptor; D004247:DNA / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000633:toxicity
chemical_list: C494773:Bak1 protein, mouse; D000090702:Constitutive Androstane Receptor; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D003208:Concanavalin A; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D004247:DNA