Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR) |
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Authors: | Xingguo Cheng Saurabh G. Vispute Jie Liu Christine Cheng Alexei Kharitonenkov Curtis D. Klaassen |
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Affiliation: | 1. Department of Pharmaceutical Sciences, St. John''s University, 8000 Utopia Parkway, Queens, NY 11439, USA;2. Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA;3. Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285, USA |
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Abstract: | 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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Keywords: | AhR, aryl hydrocarbon receptor Arnt, aryl hydrocarbon receptor nuclear translocator bDNA, branched DNA signal amplification assay BNF, β-naphthoflavone ChIP, chromatin immunoprecipitation Cyp, cytochrome p450 enzyme DEHP, diethylhexylphthalate Fgf21, fibroblast growth factor 21 PGC1α, peroxisome proliferator-activated receptor gamma coactivator protein-1alpha PPAR, peroxisome proliferator-activated receptor RLU, relative light units TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin WAT, white adipose tissue WT, Wild-type mice DRE, dioxin response element |
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