Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants
Abstract Background Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE i...
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| Language: | English |
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BMC
2024-12-01
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| Series: | Particle and Fibre Toxicology |
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| Online Access: | https://doi.org/10.1186/s12989-024-00605-6 |
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| author | Gajalakshmi Ramanathan Yuqi Zhao Rajat Gupta Siri Langmo May Bhetraratana Fen Yin Will Driscoll Jerry Ricks Allen Louie James A. Stewart Timothy R. Gould Timothy V. Larson Joel Kaufman Michael E. Rosenfeld Xia Yang Jesus A. Araujo |
| author_facet | Gajalakshmi Ramanathan Yuqi Zhao Rajat Gupta Siri Langmo May Bhetraratana Fen Yin Will Driscoll Jerry Ricks Allen Louie James A. Stewart Timothy R. Gould Timothy V. Larson Joel Kaufman Michael E. Rosenfeld Xia Yang Jesus A. Araujo |
| author_sort | Gajalakshmi Ramanathan |
| collection | DOAJ |
| description | Abstract Background Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity. Methods Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes. Results DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis. Conclusions Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway. |
| format | Article |
| id | doaj-art-bc82f9e583764a9ca993b51cbe3868de |
| institution | Kabale University |
| issn | 1743-8977 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj-art-bc82f9e583764a9ca993b51cbe3868de2025-01-05T12:05:12ZengBMCParticle and Fibre Toxicology1743-89772024-12-0121111810.1186/s12989-024-00605-6Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutantsGajalakshmi Ramanathan0Yuqi Zhao1Rajat Gupta2Siri Langmo3May Bhetraratana4Fen Yin5Will Driscoll6Jerry Ricks7Allen Louie8James A. Stewart9Timothy R. Gould10Timothy V. Larson11Joel Kaufman12Michael E. Rosenfeld13Xia Yang14Jesus A. Araujo15Division of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDepartment of Integrative Biology and Physiology, University of California-Los AngelesDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDepartment of Pathology, University of WashingtonDepartment of Pathology, University of WashingtonDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesDepartment of Environmental and Occupational Health Sciences, University of WashingtonDepartment of Civil and Environmental Engineering, University of WashingtonDepartment of Environmental and Occupational Health Sciences, University of WashingtonDepartment of Environmental and Occupational Health Sciences, University of WashingtonDepartment of Pathology, University of WashingtonDepartment of Integrative Biology and Physiology, University of California-Los AngelesDivision of Cardiology, David Geffen School of Medicine, University of California-Los AngelesAbstract Background Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity. Methods Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes. Results DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis. Conclusions Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway.https://doi.org/10.1186/s12989-024-00605-6Diesel exhaustAir pollutionLiverTranscriptomicsMetabolomicsMitochondrial dysfunction |
| spellingShingle | Gajalakshmi Ramanathan Yuqi Zhao Rajat Gupta Siri Langmo May Bhetraratana Fen Yin Will Driscoll Jerry Ricks Allen Louie James A. Stewart Timothy R. Gould Timothy V. Larson Joel Kaufman Michael E. Rosenfeld Xia Yang Jesus A. Araujo Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants Particle and Fibre Toxicology Diesel exhaust Air pollution Liver Transcriptomics Metabolomics Mitochondrial dysfunction |
| title | Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| title_full | Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| title_fullStr | Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| title_full_unstemmed | Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| title_short | Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| title_sort | integrated hepatic transcriptomics and metabolomics identify pck1 as a key factor in the broad dysregulation induced by vehicle pollutants |
| topic | Diesel exhaust Air pollution Liver Transcriptomics Metabolomics Mitochondrial dysfunction |
| url | https://doi.org/10.1186/s12989-024-00605-6 |
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