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.
Keywords: AHR; AHR, aryl hydrocarbon receptor; ALT, alanine transaminase; ANOVA, analysis of variance; AST, aspartate transaminase; AUC, area under the curve; CAR, constitutive androstane receptor; CD36, cluster of differentiation 36; CYP, cytochrome P450; EPF, enrichment by protein function; Endocrine disruption; Environmental liver disease; FDR, false discovery rate; FGF21, fibroblast growth factor 21; GCR, glucocorticoid receptor; GO, gene ontology; H&E, hematoxylin-eosin; HDL, high-density lipoprotein; HFD, high fat diet; IGF1, insulin-like growth factor 1; IL-6, interleukin 6; IPF, interaction by protein function; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; MUP, major urinary protein; NAFLD, non-alcoholic fatty liver disease; NFKBIA, nuclear factor kappa-inhibitor alpha; Nonalcoholic fatty liver disease; PAI-1, plasminogen activator inhibitor-1; PCB, polychlorinated biphenyl; PCB126; PLIN2, perilipin-2; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPARα, peroxisome proliferator-activated receptor alpha; PXR, pregnane-xenobiotic receptor; Perilipin-2; Pheromones; SGK1, serum/glucocorticoid regulated kinase; TAFLD, toxicant-associated fatty liver disease; TASH, toxicant-associated steatohepatitis; TAT, tyrosine aminotransferase; TMT, tandem mass tag; VLDL, very low-density lipoprotein; WT, wild type; ZFP125, zinc finger protein 125; miR, microRNA; nHDLc, non-HDL cholesterol.
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