Loss of the Mono-ADP-ribosyltransferase,Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality |
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Authors: | Shaimaa Ahmed Debbie Bott Alvin Gomez Laura Tamblyn Adil Rasheed Tiffany Cho Laura MacPherson Kim S Sugamori Yang Yang Denis M Grant Carolyn L Cummins Jason Matthews |
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Institution: | From the ‡Department of Pharmacology and Toxicology.;§Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada |
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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. |
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Keywords: | ADP-ribosylation aryl hydrocarbon receptor (AhR) (AHR) dioxin gene expression toxicity |
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