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Acta Pharm Sin B

Title:		Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver
Author(s):		Jin J; Wahlang B; Thapa M; Head KZ; Hardesty JE; Srivastava S; Merchant ML; Rai SN; Prough RA; Cave MC;
Address:		"Department of Pharmacology & Toxicology, the University of Louisville School of Medicine, Louisville, KY 40202, USA. Department of Endocrinology, the Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China. Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, the University of Louisville School of Medicine, Louisville, KY 40202, USA. Superfund Research Center, the University of Louisville, Louisville, KY 40202, USA. Department of Biochemistry and Molecular Genetics, the University of Louisville School of Medicine, Louisville, KY 40202, USA. Department of Bioinformatics and Biostatistics, the School of Public Health and Information Sciences, the University of Louisville, Louisville, KY 40202, USA. Centre for Agricultural Bioinformatics, ICAR-Indian Agricultural Statistics Research Institute, New Delhi 110012, India. The Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, KY 40202, USA. Division of Nephrology & Hypertension, Department of Medicine, the University of Louisville School of Medicine, Louisville, KY 40202, USA. The Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY 40202, USA. Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA. Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, Louisville, KY 40202, USA"
Journal Title:		Acta Pharm Sin B
Year:		2021
Volume:		20211021
Issue:		12
Page Number:		3806 - 3819
DOI:		10.1016/j.apsb.2021.10.014
ISSN/ISBN:		2211-3835 (Print) 2211-3843 (Electronic) 2211-3835 (Linking)
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"
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 b;"
Notes:		"PubMed-not-MEDLINEJin, Jian Wahlang, Banrida Thapa, Monika Head, Kimberly Z Hardesty, Josiah E Srivastava, Sudhir Merchant, Michael L Rai, Shesh N Prough, Russell A Cave, Matthew C eng F32 AA027950/AA/NIAAA NIH HHS/ L30 AA027913/AA/NIAAA NIH HHS/ R01 ES032189/ES/NIEHS NIH HHS/ R35 ES028373/ES/NIEHS NIH HHS/ Netherlands 2022/01/14 Acta Pharm Sin B. 2021 Dec; 11(12):3806-3819. doi: 10.1016/j.apsb.2021.10.014. Epub 2021 Oct 21"