Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants.

Publisher: BioMed Central Country of Publication: England NLM ID: 101236354 Publication Model: Electronic Cited Medium: Internet ISSN: 1743-8977 (Electronic) Linking ISSN: 17438977 NLM ISO Abbreviation: Part Fibre Toxicol Subsets: MEDLINE

Original Publication: London : BioMed Central, 2004-

Liver*/drug effects ; Liver*/metabolism ; Phosphoenolpyruvate Carboxykinase (GTP)*/genetics ; Phosphoenolpyruvate Carboxykinase (GTP)*/metabolism ; Metabolomics* ; Transcriptome*/drug effects ; Vehicle Emissions*/toxicity; Animals ; Humans ; Hep G2 Cells ; Mice, Knockout, ApoE ; Air Pollutants/toxicity ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Mice ; Lipid Metabolism/drug effects ; Mice, Inbred C57BL

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.
Competing Interests: Declarations. Ethical approval: Animal procedures were approved by the Animal Care and Use Committees of the University of Washington and UCLA. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)

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ES016959, ES029395, ES32806, ES033703 United States ES NIEHS NIH HHS; R01 ES033703 United States ES NIEHS NIH HHS; R56 ES016959 United States ES NIEHS NIH HHS; R01 ES032806 United States ES NIEHS NIH HHS; R01 ES029395 United States ES NIEHS NIH HHS; R01 ES016959 United States ES NIEHS NIH HHS

Keywords: Air pollution; Diesel exhaust; Gluconeogenesis; Glycogenolysis; Liver; Metabolomics; Mitochondrial dysfunction; Pck1; Transcriptomics

EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinase (GTP))
0 (Vehicle Emissions)
EC 4.1.1.32 (Pck1 protein, mouse)
0 (Air Pollutants)
0 (Intracellular Signaling Peptides and Proteins)
EC 4.1.1.32 (PCK1 protein, human)

Date Created: 20241229 Date Completed: 20241230 Latest Revision: 20250104

20250104

PMC11684268

10.1186/s12989-024-00605-6

39734207