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

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.

芳基烃受体（aryl hydrocarbon receptor, AHR）可介导二噁英（2,3,7,8-四氯二苯并对二噁英；TCDD）的毒性效应，这类效应在实验啮齿类动物中表现为胸腺萎缩、脂肪性肝炎以及致死性消瘦综合征。尽管二噁英毒性的具体机制仍未明确，但肝细胞中的AHR信号通路是二噁英诱导性肝毒性的必要条件。我们此前的研究表明，TCDD诱导性多聚ADP核糖聚合酶（TIPARP/PARP7/ARTD14）——一种AHR靶基因及单ADP核糖基转移酶——的缺失会增强小鼠对二噁英诱导毒性的敏感性。为验证TIPARP是肝细胞中AHR信号通路负调控因子这一假说，我们构建了Tiparp基因3号外显子两侧带有loxP位点的Tiparp^fl/fl小鼠，随后通过Cre-lox重组技术分别构建了肝细胞特异性Tiparp敲除（Tiparp^fl/flCre^Alb）与全身型Tiparp敲除（Tiparp^fl/flCre^CMV；即Tiparp^Ex3-/-）小鼠。分别单次注射10 μg/kg二噁英后，Tiparp^fl/flCre^Alb与Tiparp^Ex3-/-小鼠分别无法存活至第7天与第9天，而所有野生型（Tiparp^+/+）小鼠均可在30天给药周期中存活。与同处理条件下的野生型小鼠相比，暴露于二噁英的Tiparp^fl/flCre^Alb与Tiparp^Ex3-/-小鼠表现出更严重的脂肪性肝炎与肝毒性，具体体现为中性脂质染色更强以及血清丙氨酸氨基转移酶活性升高。此外，上述两种敲除小鼠的AHR信号通路被激活，表现为二噁英诱导的基因表达水平上调。代谢组学研究显示，与野生型小鼠相比，Tiparp^fl/flCre^Alb小鼠的肝脏提取物中脂质与氨基酸代谢发生了改变。综上，本研究数据表明TIPARP是AHR活性的重要负调控因子，且肝细胞中TIPARP的特异性缺失足以增强小鼠对二噁英诱导的脂肪性肝炎及致死毒性的敏感性。