Original articles
Jian Jin, Banrida Wahlang, Monika Thapa, Kimberly Z. Head, Josiah E. Hardesty, Sudhir Srivastava, Michael L. Merchant, Shesh N. Rai, Russell A. Prough, Matthew C. Cave. Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3806-3819

Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver
Jian Jina,b, Banrida Wahlangc,d, Monika Thapae, Kimberly Z. Headc, Josiah E. Hardestyc, Sudhir Srivastavaf,g, Michael L. Merchanth,i,j, Shesh N. Raid,f,h,j,k,l, Russell A. Proughe, Matthew C. Cavea,c,d,e,h,j,k
a. Department of Pharmacology & Toxicology, the University of Louisville School of Medicine, Louisville, KY 40202, USA;
b. Department of Endocrinology, the Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China;
c. Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, the University of Louisville School of Medicine, Louisville, KY 40202, USA;
d. Superfund Research Center, the University of Louisville, Louisville, KY 40202, USA;
e. Department of Biochemistry and Molecular Genetics, the University of Louisville School of Medicine, Louisville, KY 40202, USA;
f. Department of Bioinformatics and Biostatistics, the School of Public Health and Information Sciences, the University of Louisville, Louisville, KY 40202, USA;
g. Centre for Agricultural Bioinformatics, ICAR-Indian Agricultural Statistics Research Institute, New Delhi 110012, India;
h. The Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, KY 40202, USA;
i. Division of Nephrology & Hypertension, Department of Medicine, the University of Louisville School of Medicine, Louisville, KY 40202, USA;
j. The Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY 40202, USA;
k. Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA;
l. Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, Louisville, KY 40202, USA
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.
Key words:    AHR    Endocrine disruption    Environmental liver disease    Nonalcoholic fatty liver disease    Perilipin-2    Pheromones    PCB126   
Received: 2021-07-23     Revised: 2021-09-23
DOI: 10.1016/j.apsb.2021.10.014
Funds: This research was supported, in part, by the National Institute of Environmental Health Sciences (R35ES028373, R01ES032189, T32ES011564, P42ES023716, P30ES030283, F31ES028982 and R21ES031510, USA); the National Institute of General Medical Sciences (P20GM113226, USA); the National Institute on Alcohol Abuse and Alcoholism (P50AA024337 and 1F32AA027950, USA); the Kentucky Council on Postsecondary Education (PON2 415 1900002934, USA); and the Wendell Cherry Endowed Chair. Dr. Jin would like to acknowledge the contributions of several members of his doctoral dissertation committee who were not included as coauthors (e.g., Drs. Daniel J. Conklin, Sri Prakash Mokshagundam, Joshua L Hood, and Jonathan H. Freedman). These individuals helped to shape the direction of this research. Daniel Wilkey, Dr. Keith Cameron Falkner, Sydney E. Smith, Erica F. Daly and Steve Mahanes are also acknowledged.
Corresponding author: Matthew C. Cave,E-mail:matt.cave@louisville.edu     Email:matt.cave@louisville.edu
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Authors
Jian Jin
Banrida Wahlang
Monika Thapa
Kimberly Z. Head
Josiah E. Hardesty
Sudhir Srivastava
Michael L. Merchant
Shesh N. Rai
Russell A. Prough
Matthew C. Cave

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