Identification of the Aryl Hydrocarbon Receptor Target Gene TiPARP as a Mediator of Suppression of Hepatic Gluconeogenesis by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and of Nicotinamide as a Corrective Agent for This Effect

被引:89
作者
Diani-Moore, Silvia [1 ]
Ram, Payal [1 ]
Li, Xintian [1 ]
Mondal, Prosenjit [1 ]
Youn, Dou Yeon [1 ]
Sauve, Anthony A. [1 ]
Rifkind, Arleen B. [1 ]
机构
[1] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10065 USA
基金
美国国家卫生研究院;
关键词
POLY(ADP-RIBOSE) POLYMERASE; MAMMALIAN-CELLS; ACUTE TOXICITY; TCDD; METABOLISM; ACTIVATION; EXPRESSION; ENZYMES; ALPHA; PGC-1;
D O I
10.1074/jbc.M110.131573
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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(ADPribose) 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 gamma coactivator 1 alpha (PGC1 alpha), 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 PGC1 alpha acetylation and decreased PGC1 alpha 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 PGC1 alpha. 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 PGC1 alpha function and stability and that NAM has novel AHR antagonist activity.
引用
收藏
页码:38801 / 38810
页数:10
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