title: Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity.
abstract: Peroxisome proliferator-activated receptor-binding protein (PBP), also known as thyroid hormone receptor-associated protein 220/vitamin D receptor-interacting protein 205/mediator 1, an anchor for multisubunit mediator transcription complex, functions as a transcription coactivator for nuclear receptors. Disruption of the PBP gene results in embryonic lethality around embryonic day 11.5 by affecting placental and multiorgan development. Here, we report that targeted deletion of PBP in liver parenchymal cells (PBP(Liv-/-)) results in the abrogation of hypertrophic and hyperplastic influences in liver mediated by constitutive androstane receptor (CAR) ligands phenobarbital (PB) and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, and of acetaminophen-induced hepatotoxicity. CAR interacts with the two nuclear receptor-interacting LXXLL (L, leucine; X, any amino acid) motifs in PBP in a ligand-dependent manner. We also show that PBP interacts with the C-terminal portion of CAR, suggesting that PBP is involved in the regulation of CAR function. Although the full-length PBP only minimally increased CAR transcriptional activity, a truncated form of PBP (amino acids 487-735) functioned as a dominant negative repressor, establishing that PBP functions as a coactivator for CAR. A reduction in CAR mRNA and protein level observed in PBP(Liv-/-) mouse liver suggests that PBP may regulate hepatic CAR expression. PBP-deficient hepatocytes in liver failed to reveal PB-dependent translocation of CAR to the nucleus. Adenoviral reconstitution of PBP in PBP(Liv-/-) mouse livers restored PB-mediated nuclear translocation of CAR as well as inducibility of CYP1A2, CYP2B10, CYP3A11, and CYP7A1 expression. We conclude that transcription coactivator PBP/TRAP220/MED1 is involved in the regulation of hepatic CAR function and that PBP deficiency in liver abrogates acetaminophen hepatotoxicity.
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Sailesh
authors.initials: S
authors.lastname: Surapureddi
authors.forename: Joy
authors.initials: J
authors.lastname: Sarkar
authors.forename: Chao
authors.initials: C
authors.lastname: Qi
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.forename: Papreddy
authors.initials: P
authors.lastname: Kashireddi
authors.forename: Songtao
authors.initials: S
authors.lastname: Yu
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Cho
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001483:Base Sequence; D000090702:Constitutive Androstane Receptor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006965:Hyperplasia; D006984:Hypertrophy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D056913:Mediator Complex Subunit 1; D051379:Mice; D018345:Mice, Knockout; D009125:Muscle Relaxants, Central / Q000633:toxicity; D010243:Paralysis / Q000139:chemically induced; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015049:Zoxazolamine / Q000633:toxicity
chemical_list: D000090702:Constitutive Androstane Receptor; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D009125:Muscle Relaxants, Central; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000082:Acetaminophen; D004247:DNA; D015049:Zoxazolamine