Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).
Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).
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DOI：
10.1016/j.taap.2014.04.013
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发表时间：
2014-07-01
影响因子：
3.8
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
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作者：
Cheng, Xingguo;Vispute, Saurabh G.;Liu, Jie;Cheng, Christine;Kharitonenkov, Alexei;Klaassen, Curtis D.
二恶英（例如2，3，7，8-四氯二苯并对二恶英（TCDD））的毒性作用主要通过激活芳烃受体（AhR）来实现，这一点已得到充分证明。成纤维细胞生长因子（Fgf）21通过增加肝脏中的脂质氧化和酮生成在禁食的代谢适应中起关键作用。进行本研究以确定AhR的激活是否诱导Fgf 21表达。在小鼠肝脏中，TCDD以剂量和时间依赖性方式增加Fgf 21 mRNA。此外，TCDD显着增加Fgf 21 mRNA在培养的小鼠和人肝细胞的表达。此外，TCDD增加野生型小鼠中Fgf 21的mRNA（肝脏）和蛋白质水平（肝脏和血清），但在AhR-null小鼠中没有。染色质免疫沉淀分析表明，TCDD增加了AhR蛋白与Fgf 21启动子（−105/+1碱基对）的结合。Fgf 21基因敲除小鼠在20天内死亡，而野生型小鼠在给药后1个月仍然存活。这表明，TCDD诱导的Fgf 21表达保护免受TCDD毒性。邻苯二甲酸二乙己酯（DEHP）预处理减弱了TCDD诱导的小鼠肝脏和白色脂肪组织中Fgf 21的表达，这可能解释了先前的报告，即DEHP预处理减少了TCDD诱导的消耗。Fgf 21可能是小鼠和人肝脏AhR信号通路的靶基因。
The toxic effects of dioxins, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (−105/+1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.
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DOI：
10.1016/j.bbrc.2007.06.068
发表时间：
2007-08-24
影响因子：
3.1
作者：
Lundasen, Thomas;Hunt, Mary C.;Rudling, Mats
通讯作者：
Rudling, Mats
影响因子：
4.8
作者：
Ding, Xunshan;Lichti, Kristin;Staudinger, Jeff L.
通讯作者：
Staudinger, Jeff L.
影响因子：
3.9
作者：
Cheng, XG;Maher, J;Klaassen, CD
通讯作者：
Klaassen, CD
影响因子：
3.5
作者：
Izumiya, Yasuhiro;Bina, Holly A.;Ouchi, Noriyuki;Akasaki, Yuichi;Kharitonenkov, Alexei;Walsh, Kenneth
通讯作者：
Walsh, Kenneth
DOI：
10.1038/nrd2792
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
通讯作者：
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