title: Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.
abstract: The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling.
authors.affiliation: From the Graduate Program in Microbiology and Molecular Biology.
authors.forename: Nathaniel G
authors.initials: NG
authors.lastname: Girer
authors.affiliation: the Department of Veterinary and Biomedical Sciences, and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.affiliation: the Department of Veterinary and Biomedical Sciences, and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
authors.affiliation: the Department of Veterinary and Biomedical Sciences, and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 ghp2@psu.edu.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D005346:Fibroblast Growth Factors; D018970:Insulin-Like Growth Factor Binding Protein 1; D009687:Nuclear Proteins; D047493:PPAR alpha; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C111235:AHR protein, human; C484722:Ahr protein, mouse; C500051:Creb3l3 protein, mouse; C032231:IGFBP1 protein, human; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; C414620:fibroblast growth factor 21
keywords: aryl hydrocarbon receptor (AhR) (AHR); cAMP-responsive element-binding protein hepatocyte-specific (CREBH); carbohydrate response element-binding protein (ChREBP); endoplasmic reticulum stress (ER stress); energy metabolism; fibroblast growth factor (FGF); glucose metabolism; peroxisome proliferator-activated receptor (PPAR)