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J Biol Chem. 2015 Jul 3;290(27):16824-40. doi: 10.1074/jbc.M115.660100. Epub 2015 May 13.

Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality.

Author information

1
From the Department of Pharmacology and Toxicology.
2
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3
From the Department of Pharmacology and Toxicology, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4
From the Department of Pharmacology and Toxicology, jason.matthews@utoronto.ca.

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.

KEYWORDS:

ADP-ribosylation; aryl hydrocarbon receptor (AhR) (AHR); dioxin; gene expression; toxicity

PMID:
25975270
PMCID:
PMC4505429
DOI:
10.1074/jbc.M115.660100
[Indexed for MEDLINE]
Free PMC Article

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