AHR is a master regulator of diverse pathways in endogenous metabolism
Abstract The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Net...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-20572-2 |
| _version_ | 1811194908145352704 |
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| author | Jeffry C. Granados Kian Falah Imhoi Koo Ethan W. Morgan Gary H. Perdew Andrew D. Patterson Neema Jamshidi Sanjay K. Nigam |
| author_facet | Jeffry C. Granados Kian Falah Imhoi Koo Ethan W. Morgan Gary H. Perdew Andrew D. Patterson Neema Jamshidi Sanjay K. Nigam |
| author_sort | Jeffry C. Granados |
| collection | DOAJ |
| description | Abstract The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Network involved in inter-organ communication via metabolites and signaling molecules. Here, we use integrated omics approaches to analyze its contributions to metabolism across multiple scales from the organ to the organelle. Global metabolomics analysis of Ahr −/− mice revealed the role of AHR in the regulation of 290 metabolites involved in many biochemical pathways affecting fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis suggest that AHR plays a role in determining the hydrophobicity of metabolites and perhaps their transporter-mediated movement into and out of tissues. Of known AHR ligands, indolepropionate was the only significantly altered molecule, and it activated AHR in both human and murine cells. To gain a deeper biological understanding of AHR, we employed genome scale metabolic reconstruction to integrate knockout transcriptomics and metabolomics data, which indicated a role for AHR in regulation of organic acids and redox state. Together, the results indicate a central role of AHR in metabolism and signaling between multiple organs and across multiple scales. |
| first_indexed | 2024-04-12T00:35:09Z |
| format | Article |
| id | doaj.art-5bca312afba045ba961d8d346b2ebbad |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T00:35:09Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5bca312afba045ba961d8d346b2ebbad2022-12-22T03:55:11ZengNature PortfolioScientific Reports2045-23222022-10-0112111610.1038/s41598-022-20572-2AHR is a master regulator of diverse pathways in endogenous metabolismJeffry C. Granados0Kian Falah1Imhoi Koo2Ethan W. Morgan3Gary H. Perdew4Andrew D. Patterson5Neema Jamshidi6Sanjay K. Nigam7Department of Bioengineering, University of California San DiegoDepartments of Biology, University of California San DiegoDepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State UniversityDepartment of Biochemistry and Molecular Biology, The Pennsylvania State UniversityDepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State UniversityDepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State UniversityDepartment of Radiological Sciences, University of California Los AngelesDepartment of Pediatrics, University of California San DiegoAbstract The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Network involved in inter-organ communication via metabolites and signaling molecules. Here, we use integrated omics approaches to analyze its contributions to metabolism across multiple scales from the organ to the organelle. Global metabolomics analysis of Ahr −/− mice revealed the role of AHR in the regulation of 290 metabolites involved in many biochemical pathways affecting fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis suggest that AHR plays a role in determining the hydrophobicity of metabolites and perhaps their transporter-mediated movement into and out of tissues. Of known AHR ligands, indolepropionate was the only significantly altered molecule, and it activated AHR in both human and murine cells. To gain a deeper biological understanding of AHR, we employed genome scale metabolic reconstruction to integrate knockout transcriptomics and metabolomics data, which indicated a role for AHR in regulation of organic acids and redox state. Together, the results indicate a central role of AHR in metabolism and signaling between multiple organs and across multiple scales.https://doi.org/10.1038/s41598-022-20572-2 |
| spellingShingle | Jeffry C. Granados Kian Falah Imhoi Koo Ethan W. Morgan Gary H. Perdew Andrew D. Patterson Neema Jamshidi Sanjay K. Nigam AHR is a master regulator of diverse pathways in endogenous metabolism Scientific Reports |
| title | AHR is a master regulator of diverse pathways in endogenous metabolism |
| title_full | AHR is a master regulator of diverse pathways in endogenous metabolism |
| title_fullStr | AHR is a master regulator of diverse pathways in endogenous metabolism |
| title_full_unstemmed | AHR is a master regulator of diverse pathways in endogenous metabolism |
| title_short | AHR is a master regulator of diverse pathways in endogenous metabolism |
| title_sort | ahr is a master regulator of diverse pathways in endogenous metabolism |
| url | https://doi.org/10.1038/s41598-022-20572-2 |
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