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.
Highlights
15378 JOURNAL OF BIOLOGICAL CHEMISTRY tion factor, classically known for mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity
Using EMSA, we demonstrate that the Aryl hydrocarbon receptor (AHR)-aryl hydrocarbon receptor nuclear translocator (ARNT) heterodimer binds to a specific dioxin response elements (DRE) that overlaps binding sequences for peroxisome proliferator-activated receptor ␣ (PPAR␣), carbohydrate response element-binding protein (ChREBP), and cAMP response elementbinding protein, hepatocyte specific (CREBH)
CreAlbAhrFx/Fx Mice Exhibit Increased Expression of the Fasting-induced Hormone Fgf21 during a Non-fasted State—fibroblast growth factor 21 (FGF21) is a key regulator of the fasting response; hepatic Fgf21 expression occurs at a low basal level during a non-fasting state
Summary
CreAlbAhrFx/Fx Mice Exhibit Increased Expression of the Fasting-induced Hormone Fgf during a Non-fasted State—FGF21 is a key regulator of the fasting response; hepatic Fgf expression occurs at a low basal level during a non-fasting state. We demonstrate that AHR agonists TCDD (Fig. 2D, lanes 1–5) and indolo[3,2b]carbazole (ICZ) (Fig. 2D, lanes 6 –10) result in AHR-ARNT heterodimerization and DRE binding to the 32P-labeled Fgf oligonucleotide. Treatment with AHR agonist ICZ ablates PPAR␣-, ChREBP-, and CREBH-dependent induction (Fig. 3A), suggesting that ligand-activated AHR can interfere with the promoter-driven activation of Fgf expression by these transcription factors. Consistent with AHR activation, we observe a statistically significant increase in Cyp1a1 transcriptional levels in ICZ-treated cells (Fig. 3E). Comparable with treatment using DTT or thapsigargin, incubating Hepa-1 cells for 24 h in glucose-free medium activates ER stress and Fgf expression (Fig. 4A). Treatment with PPAR␣ ligand GW7647 activates CPT1A expression and significantly increases FGF21 expression Ͼ3-fold, whereas pretreatment of cells with AHR agonist significantly inhibits this response. Consistent with previous experiments, DTT increases FGF21 expression 69-fold, whereas a 1-h pretreatment with 500 nM ICZ significantly impairs DTT-induced FGF21 expression by 46% (Fig. 5F)
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