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

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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.

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.

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Most cited references 48

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Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study

Elliot B. Tapper, Neehar D. Parikh (2018)

Abstract Objective To describe liver disease related mortality in the United States during 1999-2016 by age group, sex, race, cause of liver disease, and geographic region. Design Observational cohort study. Setting Death certificate data from the Vital Statistics Cooperative, and population data from the US Census Bureau compiled by the Center for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research (1999-2016). Participants US residents. Main outcome measure Deaths from cirrhosis and hepatocellular carcinoma, with trends evaluated using joinpoint regression. Results From 1999 to 2016 in the US annual deaths from cirrhosis increased by 65%, to 34 174, while annual deaths from hepatocellular carcinoma doubled to 11 073. Only one subgroup—Asians and Pacific Islanders—experienced an improvement in mortality from hepatocellular carcinoma: the death rate decreased by 2.7% (95% confidence interval 2.2% to 3.3%, P<0.001) per year. Annual increases in cirrhosis related mortality were most pronounced for Native Americans (designated as “American Indians” in the census database) (4.0%, 2.2% to 5.7%, P=0.002). The age adjusted death rate due to hepatocellular carcinoma increased annually by 2.1% (1.9% to 2.3%, P<0.001); deaths due to cirrhosis began increasing in 2009 through 2016 by 3.4% (3.1% to 3.8%, P<0.001). During 2009-16 people aged 25-34 years experienced the highest average annual increase in cirrhosis related mortality (10.5%, 8.9% to 12.2%, P<0.001), driven entirely by alcohol related liver disease. During this period, mortality due to peritonitis and sepsis in the setting of cirrhosis increased substantially, with respective annual increases of 6.1% (3.9% to 8.2%) and 7.1% (6.1% to 8.4%). Only one state, Maryland, showed improvements in mortality (−1.2%, −1.7% to −0.7% per year), while many, concentrated in the south and west, observed disproportionate annual increases: Kentucky 6.8% (5.1% to 8.5%), New Mexico 6.0% (4.1% to 7.9%), Arkansas 5.7% (3.9% to 7.6%), Indiana 5.0% (3.8% to 6.1%), and Alabama 5.0% (3.2% to 6.8%). No state showed improvements in hepatocellular carcinoma related mortality, while Arizona (5.1%, 3.7% to 6.5%) and Kansas (4.3%, 2.8% to 5.8%) experienced the most severe annual increases. Conclusions Mortality due to cirrhosis has been increasing in the US since 2009. Driven by deaths due to alcoholic cirrhosis, people aged 25-34 have experienced the greatest relative increase in mortality. White Americans, Native Americans, and Hispanic Americans experienced the greatest increase in deaths from cirrhosis. Mortality due to cirrhosis is improving in Maryland but worst in Kentucky, New Mexico, and Arkansas. The rapid increase in death rates among young people due to alcohol highlight new challenges for optimal care of patients with preventable liver disease.

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Author and article information

Contributors

Matthew C. Cave

Journal

Journal ID (nlm-ta): Acta Pharm Sin B

Journal ID (iso-abbrev): Acta Pharm Sin B

Title: Acta Pharmaceutica Sinica. B

Publisher: Elsevier

ISSN (Print): 2211-3835

ISSN (Electronic): 2211-3843

Publication date PMC-release: 21 October 2021

Publication date (Print): December 2021

Publication date (Electronic): 21 October 2021

Volume: 11

Issue: 12

Pages: 3806-3819

Affiliations

[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

Author notes

[∗ ]Corresponding author. Tel.: +1 502 8525252; fax: +1 502 8528927. matt.cave@ 123456louisville.edu

Article

Publisher Item ID: S2211-3835(21)00406-8

DOI: 10.1016/j.apsb.2021.10.014

PMC ID: 8727924

SO-VID: 7485e0a0-f3fa-4b3d-94a0-d8a36affc226

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 23 July 2021

Date revision received : 23 September 2021

Date accepted : 28 September 2021

Categories

Subject: Original Article

Keywords: h&e, hematoxylin-eosin,ahr,endocrine disruption,environmental liver disease,nonalcoholic fatty liver disease,perilipin-2,pheromones,pcb126,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,fdr, false discovery rate,fgf21, fibroblast growth factor 21,igf1, insulin-like growth factor 1,il-6, interleukin 6,gcr, glucocorticoid receptor,go, gene ontology,hdl, high-density lipoprotein,hfd, high fat diet,ipf, interaction by protein function,ldl, low-density lipoprotein,mcp-1, monocyte chemoattractant protein-1,mir, microrna,mup, major urinary protein,nafld, non-alcoholic fatty liver disease,nhdlc, non-hdl cholesterol,nfkbia, nuclear factor kappa-inhibitor alpha,pai-1, plasminogen activator inhibitor-1,pcb, polychlorinated biphenyl,plin2, perilipin-2,pnpla3, patatin-like phospholipase domain-containing protein 3,pparα, peroxisome proliferator-activated receptor alpha,pxr, pregnane-xenobiotic receptor,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

Data availability:

Keywords: h&e, hematoxylin-eosin, ahr, endocrine disruption, environmental liver disease, nonalcoholic fatty liver disease, perilipin-2, pheromones, pcb126, 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, fdr, false discovery rate, fgf21, fibroblast growth factor 21, igf1, insulin-like growth factor 1, il-6, interleukin 6, gcr, glucocorticoid receptor, go, gene ontology, hdl, high-density lipoprotein, hfd, high fat diet, ipf, interaction by protein function, ldl, low-density lipoprotein, mcp-1, monocyte chemoattractant protein-1, mir, microrna, mup, major urinary protein, nafld, non-alcoholic fatty liver disease, nhdlc, non-hdl cholesterol, nfkbia, nuclear factor kappa-inhibitor alpha, pai-1, plasminogen activator inhibitor-1, pcb, polychlorinated biphenyl, plin2, perilipin-2, pnpla3, patatin-like phospholipase domain-containing protein 3, pparα, peroxisome proliferator-activated receptor alpha, pxr, pregnane-xenobiotic receptor, 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

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

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Most cited references 48

A rapid method of total lipid extraction and purification.

Universal sample preparation method for proteome analysis.

Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study

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