文章基本信息

标题：NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion
本地全文：下载
作者：Silvia Diani-Moore ; Jenny Shoots ; Rubi Singh 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2017
卷号：7
期号：1
DOI：10.1038/s41598-017-02332-9
语种：English
出版社：Springer Nature
摘要：Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a carcinogenic and highly toxic industrial byproduct that persists in the environment and produces a pleiotropic toxicity syndrome across vertebrate species that includes wasting, hepatosteatosis, and thymus atrophy. Dioxin toxicities require binding and activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. However, after nearly 50 years of study, it remains unknown how AhR activation by dioxin produces toxic effects. Here, using the chick embryo close to hatching, a well-accepted model for dioxin toxicity, we identify NAD(+) loss through PARP activation as a novel unifying mechanism for diverse effects of dioxin in vivo. We show that NAD(+) loss is attributable to increased PARP activity in thymus and liver, as cotreatment with dioxin and the PARP inhibitor PJ34 increased NAD(+) levels and prevented both thymus atrophy and hepatosteatosis. Our findings additionally support a role for decreased NAD(+) dependent Sirt6 activity in mediating dioxin toxicity following PARP activation. Strikingly, treatment in vivo with the NAD(+) repleting agent nicotinamide, a form of vitamin B3, prevented thymus atrophy and hepatosteatosis by dioxin and increased sirtuin activity, providing a therapeutic approach for preventing dioxin toxicities in vivo.