Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver
| Autor: | Banrida Wahlang, Monika Thapa, Michael L. Merchant, Jian Jin, Sudhir Srivastava, Josiah E. Hardesty, Russell A. Prough, Shesh N. Rai, Matthew C. Cave, Kimberly Z. Head |
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| Rok vydání: | 2021 |
| Předmět: |
WT
wild type TAT tyrosine aminotransferase PCB126 AHR IGF1 insulin-like growth factor 1 PCB polychlorinated biphenyl Blood lipids FGF21 fibroblast growth factor 21 miR microRNA Pheromones AHR aryl hydrocarbon receptor AUC area under the curve Liver disease HFD high fat diet AST aspartate transaminase LDL low-density lipoprotein VLDL very low-density lipoprotein Environmental liver disease General Pharmacology Toxicology and Pharmaceutics Receptor MUP major urinary protein ANOVA analysis of variance NFKBIA nuclear factor kappa-inhibitor alpha PNPLA3 patatin-like phospholipase domain-containing protein 3 biology ZFP125 zinc finger protein 125 PXR pregnane-xenobiotic receptor MCP-1 monocyte chemoattractant protein-1 respiratory system EPF enrichment by protein function IL-6 interleukin 6 nHDLc non-HDL cholesterol IPF interaction by protein function PAI-1 plasminogen activator inhibitor-1 PLIN2 perilipin-2 Proteome CYP cytochrome P450 Original Article CAR constitutive androstane receptor SGK1 serum/glucocorticoid regulated kinase NAFLD non-alcoholic fatty liver disease medicine.medical_specialty FDR false discovery rate ALT alanine transaminase Endocrine disruption HDL high-density lipoprotein H&E hematoxylin-eosin RM1-950 CD36 cluster of differentiation 36 Perilipin-2 Internal medicine medicine Nonalcoholic fatty liver disease Pheromone binding GO gene ontology TASH toxicant-associated steatohepatitis PPARα peroxisome proliferator-activated receptor alpha TAFLD toxicant-associated fatty liver disease TMT tandem mass tag medicine.disease Aryl hydrocarbon receptor Insulin receptor Endocrinology biology.protein GCR glucocorticoid receptor Therapeutics. Pharmacology Steatosis |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3806-3819 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| DOI: | 10.1016/j.apsb.2021.10.014 |
| Popis: | 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. Graphical abstract The aryl hydrocarbon receptor regulated liver metabolism and endocrine function impacting systemic energy homeostasis and body composition. This regulation appeared to involve both direct and indirect mechanisms.Image 1 |
| Databáze: | OpenAIRE |
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