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Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity
Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased s...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754190/ https://www.ncbi.nlm.nih.gov/pubmed/36520866 http://dx.doi.org/10.1371/journal.pone.0277053 |
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author | Heintz, Melissa M. Eccles, Jazmine A. Olack, Emily M. Maner-Smith, Kristal M. Ortlund, Eric A. Baldwin, William S. |
author_facet | Heintz, Melissa M. Eccles, Jazmine A. Olack, Emily M. Maner-Smith, Kristal M. Ortlund, Eric A. Baldwin, William S. |
author_sort | Heintz, Melissa M. |
collection | PubMed |
description | Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that CYP2B6 metabolizes PUFAs, with a preference for metabolism of ALA to 9-HOTrE and to a lesser extent 13-HOTrE with a preference for metabolism of PUFAs at the 9- and 13-positions. To further study the role of CYP2B6 in vivo, humanized-CYP2B6-transgenic (hCYP2B6-Tg) and Cyp2b-null mice were fed a 60% high-fat diet for 16 weeks. Compared to Cyp2b-null mice, hCYP2B6-Tg mice showed reduced weight gain and metabolic disease as measured by glucose tolerance tests, however hCYP2B6-Tg male mice showed increased liver triglycerides. Serum and liver oxylipin metabolite concentrations increased in male hCYP2B6-Tg mice, while only serum oxylipins increased in female hCYP2B6-Tg mice with the greatest increases in LA oxylipins metabolized at the 9 and 13-positions. Several of these oxylipins, specifically 9-HODE, 9-HOTrE, and 13-oxoODE, are PPAR agonists. RNA-seq data also demonstrated sexually dimorphic changes in gene expression related to nuclear receptor signaling, especially CAR > PPAR with qPCR suggesting PPARγ signaling is more likely than PPARα signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b’s. Therefore, the inhibition of CYP2B6 by xenobiotics or dietary fats can exacerbate obesity and metabolic disease potentially through disrupted PUFA metabolism and the production of key lipid metabolites. |
format | Online Article Text |
id | pubmed-9754190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97541902022-12-16 Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity Heintz, Melissa M. Eccles, Jazmine A. Olack, Emily M. Maner-Smith, Kristal M. Ortlund, Eric A. Baldwin, William S. PLoS One Research Article Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that CYP2B6 metabolizes PUFAs, with a preference for metabolism of ALA to 9-HOTrE and to a lesser extent 13-HOTrE with a preference for metabolism of PUFAs at the 9- and 13-positions. To further study the role of CYP2B6 in vivo, humanized-CYP2B6-transgenic (hCYP2B6-Tg) and Cyp2b-null mice were fed a 60% high-fat diet for 16 weeks. Compared to Cyp2b-null mice, hCYP2B6-Tg mice showed reduced weight gain and metabolic disease as measured by glucose tolerance tests, however hCYP2B6-Tg male mice showed increased liver triglycerides. Serum and liver oxylipin metabolite concentrations increased in male hCYP2B6-Tg mice, while only serum oxylipins increased in female hCYP2B6-Tg mice with the greatest increases in LA oxylipins metabolized at the 9 and 13-positions. Several of these oxylipins, specifically 9-HODE, 9-HOTrE, and 13-oxoODE, are PPAR agonists. RNA-seq data also demonstrated sexually dimorphic changes in gene expression related to nuclear receptor signaling, especially CAR > PPAR with qPCR suggesting PPARγ signaling is more likely than PPARα signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b’s. Therefore, the inhibition of CYP2B6 by xenobiotics or dietary fats can exacerbate obesity and metabolic disease potentially through disrupted PUFA metabolism and the production of key lipid metabolites. Public Library of Science 2022-12-15 /pmc/articles/PMC9754190/ /pubmed/36520866 http://dx.doi.org/10.1371/journal.pone.0277053 Text en © 2022 Heintz et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Heintz, Melissa M. Eccles, Jazmine A. Olack, Emily M. Maner-Smith, Kristal M. Ortlund, Eric A. Baldwin, William S. Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title | Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title_full | Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title_fullStr | Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title_full_unstemmed | Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title_short | Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
title_sort | human cyp2b6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754190/ https://www.ncbi.nlm.nih.gov/pubmed/36520866 http://dx.doi.org/10.1371/journal.pone.0277053 |
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