Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression

Nathaniel Girer, Iain A. Murray, Curtis J. Omiecinski, Gary H. Perdew

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 (CreAlb AhrFx/Fx ). Compared with the congenic parental strain (AhrFx/Fx ), non-fasted CreAlb AhrFx/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 elementbinding 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.

Original languageEnglish (US)
Pages (from-to)15378-15387
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number29
DOIs
StatePublished - Jul 15 2016
Externally publishedYes

Fingerprint

Aryl Hydrocarbon Receptors
Liver
Peroxisome Proliferator-Activated Receptors
Hepatocytes
Cyclic AMP Response Element-Binding Protein
Dioxins
Response Elements
Homeostasis
Obesity
Carbohydrates
fibroblast growth factor 21
Physiological Phenomena
Nutrition
Knockout Mice
Fasting
Proteins
Transcription Factors
Genes
Chemical activation
Diet

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression. / Girer, Nathaniel; Murray, Iain A.; Omiecinski, Curtis J.; Perdew, Gary H.

In: Journal of Biological Chemistry, Vol. 291, No. 29, 15.07.2016, p. 15378-15387.

Research output: Contribution to journalArticle

Girer, Nathaniel ; Murray, Iain A. ; Omiecinski, Curtis J. ; Perdew, Gary H. / Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 29. pp. 15378-15387.
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