Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA.
J Biol Chem. 2010 Dec 10;285(50):38801-10. doi: 10.1074/jbc.M110.131573. Epub 2010 Sep 28.
The environmental toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin) produces diverse toxic effects including a lethal wasting syndrome whose hallmark is suppressed hepatic gluconeogenesis. All TCDD toxicities require activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Whereas the mechanism for AHR induction of target genes is well understood, it is not known how AHR activation produces any TCDD toxicity. This report identifies for the first time an AHR target gene, TiPARP (TCDD-inducible poly(ADP-ribose) polymerase, PARP7) that can mediate a TCDD toxicity, i.e. suppression of hepatic gluconeogenesis. TCDD suppressed hepatic glucose production, expression of key gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), and NAD(+) levels, and increased PARP activity and TiPARP expression. TCDD also increased acetylation and ubiquitin-dependent proteosomal degradation of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α), a coactivator of PEPCK and G6Pase transcription. TiPARP overexpression reproduced TCDD effects on glucose output and NAD(+) levels whereas TiPARP silencing diminished them. TiPARP overexpression also increased PGC1α acetylation and decreased PGC1α levels. In contrast, silencing of cytochromes P450 (CYP) 1A, main AHR-induced genes, did not alter TCDD suppression of gluconeogenesis. The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD(+), and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD(+) levels and suppression of AHR target gene induction. The results reveal that TiPARP can mediate a TCDD effect, that the AHR is linked to PGC1α function and stability and that NAM has novel AHR antagonist activity.
环境毒素 TCDD（2,3,7,8-四氯二苯并对二恶英，二恶英）产生多种毒性作用，包括致命的消瘦综合征，其特征是肝糖异生受到抑制。所有 TCDD 的毒性都需要激活芳香烃受体（AHR），一种配体激活的转录因子。虽然 AHR 诱导靶基因的机制已经很清楚，但尚不清楚 AHR 激活如何产生任何 TCDD 毒性。本报告首次确定了 AHR 靶基因 TiPARP（TCDD 诱导的多聚（ADP-核糖）聚合酶，PARP7），它可以介导 TCDD 毒性，即抑制肝糖异生。TCDD 抑制肝葡萄糖生成、关键糖异生基因（磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）的表达以及 NAD+水平，并增加 PARP 活性和 TiPARP 表达。TCDD 还增加了过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC1α）的乙酰化和泛素依赖性蛋白酶体降解，PGC1α 是 PEPCK 和 G6Pase 转录的共激活因子。TiPARP 过表达再现了 TCDD 对葡萄糖输出和 NAD+水平的影响，而 TiPARP 沉默则减弱了这些影响。TiPARP 过表达还增加了 PGC1α 的乙酰化并降低了 PGC1α 的水平。相比之下，细胞色素 P450（CYP）1A 的沉默，主要的 AHR 诱导基因，并没有改变 TCDD 对糖异生的抑制作用。维生素 B3 成分烟酰胺（NAM）可防止 TCDD 抑制葡萄糖输出、NAD+和糖异生基因，并稳定 PGC1α。NAM 的纠正作用可以归因于 NAD+水平的增加和 AHR 靶基因诱导的抑制。结果表明，TiPARP 可以介导 TCDD 的作用，AHR 与 PGC1α 的功能和稳定性有关，而 NAM 具有新型的 AHR 拮抗剂活性。
