Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver

Abstract

Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr –/– mice (Taconic) were fed a control diet and exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets ( Cyp1a1 and Cyp1a2 ) in WT but not Ahr –/– . Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr –/– . The liver proteome was impacted more so by Ahr –/– genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr -dependent. Ahr principally regulated liver metabolism ( e . g ., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response ( e . g ., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.

The environmental pollutant, polychlorinated biphenyl 126, alters liver function in a rodent model of alcohol‐associated liver disease

“…The observed albumin reduction appears to be a class effect for dioxin-like molecules as similar results have been published for the prototypical Ahr ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, in mice fed a standard rodent diet (Nault et al, 2017). However, hepatic albumin protein abundance was increased in vivo in Ahr knockout mice fed a control diet in another secondary analysis of our previously published proteomics data (p = 0.0006, data not shown) (Jin et al, 2021). While environmental dioxin exposures appear to regulate key liver functions such as albumin production in model systems, more mechanistic and confirmatory human data are required.…”

Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons

“…To this purpose, neurons were stained for AhR after a 90 min treatment with each ligand. This time point selection was based on previous AhR translocation studies in hepatocytes [ 42 ]. As shown in Figure 5 , AhR staining in the nucleus was increased by all treatments as compared to DMSO controls, with TCDD-treated neurons showing the greater increase.…”

“…Human iPSCs (hiPSCs) were maintained and differentiated according to an established protocol [ 42 , 52 ]. After maintaining the hiPSCs culture in Knockout Serum Replacement (KOSR) medium for 7 days, embryoid bodies (EB) formed, and they were transferred onto the gelatin (0.1%) coated plates.…”

The Function of Xenobiotic Receptors in Metabolic Diseases

“…In AHR whole-body knockout mice, adiposity was increased and was accompanied by decreased glucose tolerance. Liver steatosis was also accelerated with increased hepatic triglyceride accumulation and decreased blood lipids (Jin et al, 2021). Treatment with an AHR agonist alleviates insulin resistance and serum and liver triglyceride content in diabetic mice (Natividad et al, 2018).…”