title: Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality.
abstract: The aryl hydrocarbon receptor (AHR) mediates the toxic effects of the environmental contaminant dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a range of toxic responses, including hepatic damage, steatohepatitis, and a lethal wasting syndrome; however, the mechanisms are still unknown. Here, we show that the loss of TCDD-inducible poly(ADP-ribose) polymerase (Tiparp), an ADP-ribosyltransferase and AHR repressor, increases sensitivity to dioxin-induced toxicity, steatohepatitis, and lethality. Tiparp(-/-) mice given a single injection of 100 μg/kg dioxin did not survive beyond day 5; all Tiparp(+/+) mice survived the 30-day treatment. Dioxin-treated Tiparp(-/-) mice exhibited increased liver steatosis and hepatotoxicity. Tiparp ADP-ribosylated AHR but not its dimerization partner, the AHR nuclear translocator, and the repressive effects of TIPARP on AHR were reversed by the macrodomain containing mono-ADP-ribosylase MACROD1 but not MACROD2. These results reveal previously unidentified roles for Tiparp, MacroD1, and ADP-ribosylation in AHR-mediated steatohepatitis and lethality in response to dioxin.
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Debbie
authors.initials: D
authors.lastname: Bott
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Alvin
authors.initials: A
authors.lastname: Gomez
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Adil
authors.initials: A
authors.lastname: Rasheed
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cho
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Laura
authors.initials: L
authors.lastname: MacPherson
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Sugamori
authors.affiliation: From the Department of Pharmacology and Toxicology.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Department of Pharmacology and Toxicology, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Denis M
authors.initials: DM
authors.lastname: Grant
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.affiliation: From the Department of Pharmacology and Toxicology, jason.matthews@utoronto.ca.
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004147:Dioxins; D011065:Poly(ADP-ribose) Polymerases; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C000594530:2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase, mouse
keywords: ADP-ribosylation; aryl hydrocarbon receptor (AhR) (AHR); dioxin; gene expression; toxicity