Data from: Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome
Hutin, David, University of Toronto
Tamblyn, Laura, University of Toronto
Gomez, Alvin, University of Toronto
Grimaldi, Giulia, University of Toronto
Soelding, Helen, University of Toronto
Cho, Tiffany, University of Toronto
Ahmed, Shaimaa, University of Toronto
Lucas, Christin, University of Oslo
Kanduri, Chakravarthi, University of Oslo
Grant, Denis M., University of Toronto
Matthews, Jason, University of Toronto, University of Oslo
Soedling, Helen, University of Toronto
Published Jun 04, 2018 on Dryad.
Cite this dataset
Hutin, David et al. (2018). Data from: Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome [Dataset]. Dryad. https://doi.org/10.5061/dryad.qd7t1s8
The aryl hydrocarbon receptor (AHR) mediates the toxic effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), which include thymic atrophy, steatohepatitis, and a lethal wasting syndrome in laboratory rodents. Although the mechanisms of dioxin toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We previously reported that loss of TCDD-inducible poly(ADP-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-ADP-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities. To test the hypothesis that TIPARP is a negative regulator of AHR signaling in hepatocytes, we generated Tiparpfl/fl mice in which exon 3 of Tiparp is flanked by loxP sites, followed by Cre-lox technology to create hepatocyte-specific (Tiparpfl/flCreAlb) and whole-body (Tiparpfl/flCreCMV; TiparpEx3-/-) Tiparp null mice. Tiparpfl/flCreAlb and TiparpEx3-/- mice given a single injection of 10 g/kg dioxin did not survive beyond day 7 and 9, respectively, while all Tiparp+/+ mice survived the 30-day treatment. Dioxin-exposed Tiparpfl/flCreAlb and TiparpEx3-/- mice had increased steatohepatitis and hepatotoxicity as indicated by greater staining of neutral lipids and serum alanine aminotransferase activity than similarly treated wild-type mice. Tiparpfl/flCreAlb and TiparpEx3-/- mice exhibited augmented AHR signalling, denoted by increased dioxin-induced gene expression. Metabolomic studies revealed alterations in lipid and amino acid metabolism in liver extracts from Tiparpfl/flCreAlb mice compared with wild-type mice. Taken together, these data illustrate that TIPARP is an important negative regulator of AHR activity, and that its specific loss in hepatocytes is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality.
Supplementary Table S1
Supplementary Table S1 containing genotyping and qPCR primers.
Supplemental Table 1.pdf
Supplementary Figures S1 to S3
This is a single file that contains supplementary figure S1 which describes the truncated Tiparp protein resulting from exon 3 excision. It contains supplementary figure S2 and S3 that show the hepatic inflammation and hepatosteatosis in TiparpEx3-/- mice.
Suppl figures 1-3.pdf
Supplementary Tables S2 to S7
This excel file contains metabolomic data that is presented in supplementary tables S2 to S7.