Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).
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 200μg/kg of TCDD died within 20days, 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.
Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA. Electronic address: chengx@stjohns.edu.
Xingguo
X
Cheng
Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Saurabh G
SG
Vispute
Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Jie
J
Liu
Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285, USA.
Christine
C
Cheng
Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285, USA.
Alexei
A
Kharitonenkov
Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Electronic address: curtisklaassenphd@gmail.com.
Curtis D
CD
Klaassen
D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D004051:Diethylhexyl Phthalate; D005346:Fibroblast Growth Factors; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse; C414620:fibroblast growth factor 21
AhR; DEHP; Fgf21; Liver; TCDD; White adipose tissue