{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T08:20:12Z","timestamp":1782548412048,"version":"3.54.5"},"reference-count":101,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30ES020957"],"award-info":[{"award-number":["P30ES020957"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R00ES028734"],"award-info":[{"award-number":["R00ES028734"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006710","name":"Wayne State University","doi-asserted-by":"publisher","award":["Office of the Vice President for Research"],"award-info":[{"award-number":["Office of the Vice President for Research"]}],"id":[{"id":"10.13039\/100006710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>The hepatic xenobiotic metabolizing enzyme flavin-containing monooxygenase 3 (FMO3) has been implicated in the development of cardiometabolic disease primarily due to its enzymatic product trimethylamine-N oxide (TMAO), which has recently been shown to be associated with multiple chronic diseases, including kidney and coronary artery diseases. Although TMAO may have causative roles as a pro-inflammatory mediator, the possibility for roles in metabolic disease for FMO3, irrespective of TMAO formation, does exist. We hypothesized that FMO3 may interact with other proteins known to be involved in cardiometabolic diseases and that modulating the expression of FMO3 may impact on these interaction partners. Here, we combine a co-immunoprecipitation strategy coupled to unbiased proteomic workflow to report a novel protein:protein interaction network for FMO3. We identified 51 FMO3 protein interaction partners, and through gene ontology analysis, have identified urea cycle as an enriched pathway. Using mice deficient in FMO3 on two separate backgrounds, we validated and further investigated expressional and functional associations between FMO3 and the identified urea cycle genes. FMO3-deficient mice showed hepatic overexpression of carbamoylphosphate synthetase (CPS1), the rate-limiting gene of urea cycle, and increased hepatic urea levels, especially in mice of FVB (Friend leukemia virus B strain) background. Finally, overexpression of FMO3 in murine AML12 hepatocytes led to downregulation of CPS1. Although there is past literature linking TMAO to urea cycle, this is the first published work showing that FMO3 and CPS1 may directly interact, implicating a role for FMO3 in chronic kidney disease irrespective of TMAO formation.<\/jats:p>","DOI":"10.3390\/toxics10020060","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T01:43:27Z","timestamp":1643420607000},"page":"60","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle"],"prefix":"10.3390","volume":"10","author":[{"given":"Zhao","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-9846","authenticated-orcid":false,"given":"Paul","family":"Stemmer","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5583-8092","authenticated-orcid":false,"given":"Michael","family":"Petriello","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA"},{"name":"Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1080\/00498254.2019.1643515","article-title":"Flavin-containing monooxygenase 3 (FMO3): Genetic variants and their consequences for drug metabolism and disease","volume":"50","author":"Phillips","year":"2020","journal-title":"Xenobiotica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/jcpt.13315","article-title":"Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin","volume":"46","author":"Scimone","year":"2021","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.tips.2008.03.004","article-title":"Flavin-containing monooxygenases: Mutations, disease and drug response","volume":"29","author":"Phillips","year":"2008","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cmet.2012.12.011","article-title":"Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation","volume":"17","author":"Bennett","year":"2013","journal-title":"Cell Metab."},{"key":"ref_5","first-page":"284","article-title":"Expression of two different FMOs in sheep liver","volume":"26","author":"Lattard","year":"1998","journal-title":"Drug Metab. Dispos."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0006-2952(02)00886-9","article-title":"Physiological factors affecting the expression of FMO1 and FMO3 in the rat liver and kidney","volume":"63","author":"Lattard","year":"2002","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1124\/dmd.30.2.119","article-title":"Cloning, sequencing, and tissue-dependent expression of flavin-containing monooxygenase (FMO) 1 and FMO3 in the dog","volume":"30","author":"Lattard","year":"2002","journal-title":"Drug Metab. Dispos."},{"key":"ref_8","first-page":"46","article-title":"Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes","volume":"27","author":"Ripp","year":"1999","journal-title":"Drug Metab. Dispos."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jnutbio.2016.03.016","article-title":"Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors","volume":"33","author":"Petriello","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_10","first-page":"2928","article-title":"Activity of the carbamyl phosphate synthetase I promoter in liver nuclear extracts is dependent on a cis-acting C\/EBP recognition element","volume":"9","author":"Howell","year":"1989","journal-title":"Mol. Cell. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1146\/annurev-med-060513-093205","article-title":"The gut microbial endocrine organ: Bacterially derived signals driving cardiometabolic diseases","volume":"66","author":"Brown","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature09922","article-title":"Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease","volume":"472","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Donato, L., Alibrandi, S., Scimone, C., Castagnetti, A., Rao, G., Sidoti, A., and D\u2019Angelo, R. (2021). Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU. J. Pers. Med., 11.","DOI":"10.3390\/jpm11020087"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.envres.2018.01.007","article-title":"Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants","volume":"162","author":"Petriello","year":"2018","journal-title":"Environ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Seldin, M.M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S.L., Lusis, A.J., and Shih, D.M. (2016). Trimethylamine N-Oxide Promotes Vascular Inflammation through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-kappaB. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.115.002767"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000484623","article-title":"Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction","volume":"44","author":"Boini","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, X., Geng, J., Zhao, J., Ni, Q., Zhao, C., Zheng, Y., Chen, X., and Wang, L. (2019). Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00866"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/s41430-018-0190-2","article-title":"Fish consumption and risk of stroke, coronary heart disease, and cardiovascular mortality in a Dutch population with low fish intake","volume":"72","author":"Hengeveld","year":"2018","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1001\/jamainternmed.2019.6969","article-title":"Associations of Processed Meat, Unprocessed Red Meat, Poultry, or Fish Intake With Incident Cardiovascular Disease and All-Cause Mortality","volume":"180","author":"Zhong","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1001\/jamainternmed.2021.0036","article-title":"Associations of Fish Consumption With Risk of Cardiovascular Disease and Mortality Among Individuals with or without Vascular Disease from 58 Countries","volume":"181","author":"Mohan","year":"2021","journal-title":"JAMA Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhang, B., Xiong, K., Cai, J., and Ma, A. (2020). Fish Consumption and Coronary Heart Disease: A Meta-Analysis. Nutrients, 12.","DOI":"10.3390\/nu12082278"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1093\/ajcn\/80.3.626","article-title":"Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease","volume":"80","author":"Erkkila","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1021\/ja004206b","article-title":"The molecular mechanism of stabilization of proteins by TMAO and its ability to counteract the effects of urea","volume":"124","author":"Zou","year":"2002","journal-title":"J. Am. Chem. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8805","DOI":"10.1021\/acs.jpcb.8b04388","article-title":"Noncovalent Interactions between Trimethylamine N-Oxide (TMAO), Urea, and Water","volume":"122","author":"Zetterholm","year":"2018","journal-title":"J. Phys. Chem. B"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hartiala, J.A., Tang, W.H., Wang, Z., Crow, A.L., Stewart, A.F., Roberts, R., McPherson, R., Erdmann, J., Willenborg, C., and Hazen, S.L. (2016). Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat. Commun., 7.","DOI":"10.1038\/ncomms10558"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Catucci, G., Querio, G., Sadeghi, S.J., Gilardi, G., and Levi, R. (2019). Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It. Catalysts, 9.","DOI":"10.3390\/catal9121028"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cca.2020.04.015","article-title":"Recent advances in robotic protein sample preparation for clinical analysis and other biomedical applications","volume":"507","author":"Alexovic","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cels.2020.03.003","article-title":"BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain","volume":"10","author":"Pourhaghighi","year":"2020","journal-title":"Cell Syst."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Eid, T., Hassel, B., and Danbolt, N.C. (2020). Novel aspects of glutamine synthetase in ammonia homeostasis. Neurochem. Int., 140.","DOI":"10.1016\/j.neuint.2020.104809"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng1297-491","article-title":"Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome","volume":"17","author":"Dolphin","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.abb.2007.04.014","article-title":"Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria","volume":"464","author":"Yeung","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/0167-4889(91)90082-9","article-title":"Activation of protein kinase C is not required for glyceraldehyde-stimulated insulin secretion from rat islets","volume":"1095","author":"Persaud","year":"1991","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","unstructured":"McQueen, C.A. (2010). Monoamine Oxidases and Flavin-Containing Monooxygenases. Comprehensive Toxicology, Elsevier. [2nd ed.]."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14668","DOI":"10.1038\/s41598-017-15224-9","article-title":"Inactivation mechanism of N61S mutant of human FMO3 towards trimethylamine","volume":"7","author":"Gao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Alibrandi, S., Nicita, F., Donato, L., Scimone, C., Rinaldi, C., D\u2019Angelo, R., and Sidoti, A. (2021). Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules, 26.","DOI":"10.3390\/molecules26227045"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.3390\/ijms14022707","article-title":"Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors","volume":"14","author":"Catucci","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/bcpt.13089","article-title":"Flavin-Containing Monooxygenase 3 Polymorphic Variants Significantly Affect Clearance of Tamoxifen and Clomiphene","volume":"123","author":"Catucci","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/j.ijbiomac.2020.08.032","article-title":"Ligand stabilization and effect on unfolding by polymorphism in human flavin-containing monooxygenase 3","volume":"162","author":"Catucci","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrmicro.2017.149","article-title":"Microbial modulation of cardiovascular disease","volume":"16","author":"Brown","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11739-020-02470-5","article-title":"TMAO as a biomarker of cardiovascular events: A systematic review and meta-analysis","volume":"16","author":"Guasti","year":"2021","journal-title":"Intern. Emerg. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1517\/17425255.3.6.831","article-title":"Flavin-containing monooxygenase 3 and human disease","volume":"3","author":"Motika","year":"2007","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1016\/j.celrep.2017.05.077","article-title":"The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue","volume":"19","author":"Schugar","year":"2017","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/toxsci\/kfx180","article-title":"Editor\u2019s Highlight: PCB126 Exposure Increases Risk for Peripheral Vascular Diseases in a Liver Injury Mouse Model","volume":"160","author":"Wahlang","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1111\/febs.12744","article-title":"Weak protein complexes: Challenging to study but essential for life","volume":"281","author":"Qin","year":"2014","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6776","DOI":"10.1073\/pnas.1700818114","article-title":"Weak protein-protein interactions in live cells are quantified by cell-volume modulation","volume":"114","author":"Sukenik","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1242\/jcs.058636","article-title":"ERMES-mediated ER-mitochondria contacts: Molecular hubs for the regulation of mitochondrial biology","volume":"123","author":"Kornmann","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/nrm3440","article-title":"Endoplasmic reticulum-mitochondria contacts: Function of the junction","volume":"13","author":"Rowland","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/s41419-018-0416-1","article-title":"The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: An update","volume":"9","author":"Rieusset","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.bbamcr.2019.01.009","article-title":"ER-mitochondria interactions: Both strength and weakness within cancer cells","volume":"1866","author":"Lalli","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xu, L., Wang, X., and Tong, C. (2020). Endoplasmic Reticulum-Mitochondria Contact Sites and Neurodegeneration. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00428"},{"key":"ref_51","unstructured":"Xu, Z. (2017). Flavin-Containing Monooxygenase-3 and 5: Tissue Distribution, Age-Related Expression and Regulation by Endoplasmic Reticulum Stress. [Master\u2019s Thesis, University of Rhode Island]."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1124\/dmd.105.006171","article-title":"Quantitative analysis of FMO gene mRNA levels in human tissues","volume":"34","author":"Zhang","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","unstructured":"Gearing, M.E. (2017). Novel Mediators of Diabetes-Associated Cardiovascular Disease, Harvard University."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.bcp.2008.05.002","article-title":"Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT\/enhancer-binding protein beta (C\/EBPbeta) liver inhibitory and liver activating proteins","volume":"76","author":"Klick","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1124\/dmd.108.023457","article-title":"Aryl hydrocarbon receptor-dependent induction of flavin-containing monooxygenase mRNAs in mouse liver","volume":"36","author":"Celius","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1124\/mol.105.018705","article-title":"Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries","volume":"69","author":"Tijet","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0167-4838(93)90138-H","article-title":"Purification of macaque liver flavin-containing monooxygenase: A form of the enzyme related immunochemically to an isozyme expressed selectively in adult human liver","volume":"1162","author":"Sadeque","year":"1993","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.bcp.2004.02.036","article-title":"Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos)","volume":"68","author":"Janmohamed","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6498","DOI":"10.1038\/ncomms7498","article-title":"Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis","volume":"6","author":"Miao","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1006\/abbi.1997.9965","article-title":"Regulation of mouse liver flavin-containing monooxygenases 1 and 3 by sex steroids","volume":"342","author":"Falls","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1073\/pnas.91.2.674","article-title":"Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha","volume":"91","author":"Wu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Sefried, S., Haring, H.U., Weigert, C., and Eckstein, S.S. (2018). Suitability of hepatocyte cell lines HepG2, AML12 and THLE-2 for investigation of insulin signalling and hepatokine gene expression. Open Biol., 8.","DOI":"10.1098\/rsob.180147"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1194\/jlr.M051680","article-title":"Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis","volume":"56","author":"Shih","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"931","DOI":"10.18632\/aging.102666","article-title":"Upregulation of flavin-containing monooxygenase 3 mimics calorie restriction to retard liver aging by inducing autophagy","volume":"12","author":"Guo","year":"2020","journal-title":"Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.celrep.2014.12.036","article-title":"The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance","volume":"10","author":"Warrier","year":"2015","journal-title":"Cell Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/ATVBAHA.119.313414","article-title":"Trimethylamine-N-Oxide Promotes Vascular Calcification through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-kappaB (Nuclear Factor kappaB) Signals","volume":"40","author":"Zhang","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cell.2016.02.011","article-title":"Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk","volume":"165","author":"Zhu","year":"2016","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.cmet.2019.08.021","article-title":"Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction","volume":"30","author":"Chen","year":"2019","journal-title":"Cell Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.cmet.2009.03.003","article-title":"Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-\/- and Ldlr-\/- mice lacking CHOP","volume":"9","author":"Thorp","year":"2009","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tam, A.B., Mercado, E.L., Hoffmann, A., and Niwa, M. (2012). ER stress activates NF-kappaB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045078"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e1879","DOI":"10.1038\/cddis.2015.248","article-title":"ER stress induces NLRP3 inflammasome activation and hepatocyte death","volume":"6","author":"Lebeaupin","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2018.06.023","article-title":"Urea cycle dysregulation in non-alcoholic fatty liver disease","volume":"69","author":"Heeboll","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1161\/ATVBAHA.119.312592","article-title":"Genetic Deficiency of Flavin-Containing Monooxygenase 3 (Fmo3) Protects against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels-Brief Report","volume":"39","author":"Shih","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.kint.2019.04.031","article-title":"Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease","volume":"96","author":"Balmer","year":"2019","journal-title":"Kidney Int."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zaidan, M., Burtin, M., Zhang, J.D., Blanc, T., Barre, P., Garbay, S., Nguyen, C., Vasseur, F., Yammine, L., and Germano, S. (2020). Signaling pathways predisposing to chronic kidney disease progression. JCI Insight, 5.","DOI":"10.1172\/jci.insight.126183"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1053\/j.gastro.2009.02.064","article-title":"Y-box binding protein-1 down-regulates expression of carbamoyl phosphate synthetase-I by suppressing CCAAT enhancer-binding protein-alpha function in mice","volume":"137","author":"Chen","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0014-5793(01)02320-1","article-title":"CCAAT\/enhancer-binding protein beta is required for activation of genes for ornithine cycle enzymes by glucocorticoids and glucagon in primary-cultured hepatocytes","volume":"494","author":"Kimura","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6305","DOI":"10.1128\/MCB.18.11.6305","article-title":"Glucocorticoid receptor, C\/EBP, HNF3, and protein kinase A coordinately activate the glucocorticoid response unit of the carbamoylphosphate synthetase I gene","volume":"18","author":"Christoffels","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.biochi.2006.06.009","article-title":"In vivo footprinting of the carbamoylphosphate synthetase I cAMP-response unit indicates important roles for FoxA and PKA in formation of the enhanceosome","volume":"88","author":"Hoogenkamp","year":"2006","journal-title":"Biochimie"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1742-4658.2006.05561.x","article-title":"Hepatocyte-specific interplay of transcription factors at the far-upstream enhancer of the carbamoylphosphate synthetase gene upon glucocorticoid induction","volume":"274","author":"Hoogenkamp","year":"2007","journal-title":"FEBS J."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Singh, C., Benos, A., Grenell, A., Tran, V., Hanna, D., Anand-Apte, B., Brunengraber, H., and Sears, J.E. (2021). The urea cycle is transcriptionally controlled by hypoxia-inducible factors. bioRxiv.","DOI":"10.1101\/2021.01.25.428152"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1006\/mgme.2000.3093","article-title":"Antagonizing effect of AP-1 on glucocorticoid induction of urea cycle enzymes: A study of hyperammonemia in carnitine-deficient, juvenile visceral steatosis mice","volume":"71","author":"Saheki","year":"2000","journal-title":"Mol. Genet. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s41586-019-0996-7","article-title":"p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis","volume":"567","author":"Li","year":"2019","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.ajpath.2010.10.023","article-title":"DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma","volume":"178","author":"Liu","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"45704","DOI":"10.1074\/jbc.M102766200","article-title":"Regulation of mitochondrial carbamoyl-phosphate synthetase 1 activity by active site fatty acylation","volume":"276","author":"Corvi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1042\/BJ20100791","article-title":"Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation","volume":"433","author":"Kendrick","year":"2011","journal-title":"Biochem. J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cmet.2014.03.014","article-title":"Lysine glutarylation is a protein posttranslational modification regulated by SIRT5","volume":"19","author":"Tan","year":"2014","journal-title":"Cell Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8128","DOI":"10.1111\/jcmm.14683","article-title":"Caspase recruitment domain family member 10 regulates carbamoyl phosphate synthase 1 and promotes cancer growth in bladder cancer cells","volume":"23","author":"Liu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3382\/ps\/pew285","article-title":"Effect of alpha-lipoic acid on relieving ammonia stress and hepatic proteomic analyses of broilers","volume":"96","author":"Lu","year":"2017","journal-title":"Poult. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.snb.2006.10.045","article-title":"Ammonia bio-sniffer with flavin-containing monooxygenase","volume":"123","author":"Saito","year":"2007","journal-title":"Sens. Actuat. B Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s11248-006-9056-9","article-title":"Effects of FVB\/NJ and C57Bl\/6J strain backgrounds on mammary tumor phenotype in inducible nitric oxide synthase deficient mice","volume":"16","author":"Davie","year":"2007","journal-title":"Transgenic Res."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Szade, A., Nowak, W.N., Szade, K., Gese, A., Czypicki, R., Was, H., Dulak, J., and Jozkowicz, A. (2015). Effect of crossing C57BL\/6 and FVB mouse strains on basal cytokine expression. Mediat. Inflamm., 2015.","DOI":"10.1155\/2015\/762419"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ostergren, C., Shim, J., Larsen, J.V., Nielsen, L.B., and Bentzon, J.F. (2015). Genetic analysis of ligation-induced neointima formation in an F2 intercross of C57BL\/6 and FVB\/N inbred mouse strains. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121899"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/j.1399-6576.2006.001002.x","article-title":"Genetic background differences between FVB and C57BL\/6 mice affect hypnotic susceptibility to pentobarbital, ketamine and nitrous oxide, but not isoflurane","volume":"50","author":"Sato","year":"2006","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/CIRCRESAHA.116.305360","article-title":"Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease","volume":"116","author":"Tang","year":"2015","journal-title":"Circ. Res."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Missailidis, C., Hallqvist, J., Qureshi, A.R., Barany, P., Heimburger, O., Lindholm, B., Stenvinkel, P., and Bergman, P. (2016). Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0141738"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1152\/physrev.00045.2009","article-title":"Gut microbiota in health and disease","volume":"90","author":"Sekirov","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Chen, Z., Ruan, J., Li, D., Wang, M., Han, Z., Qiu, W., and Wu, G. (2020). The Role of Intestinal Bacteria and Gut-Brain Axis in Hepatic Encephalopathy. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.595759"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/j.jceh.2014.12.003","article-title":"Gut microbiota: Its role in hepatic encephalopathy","volume":"5","author":"Rai","year":"2015","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14162","DOI":"10.1038\/s41598-021-93299-1","article-title":"The ammonia oxidizing bacterium Nitrosomonas eutropha blocks T helper 2 cell polarization via the anti-inflammatory cytokine IL-10","volume":"11","author":"Maura","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/gut.14.3.171","article-title":"Ammonia production by intestinal bacteria","volume":"14","author":"Vince","year":"1973","journal-title":"Gut"}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/10\/2\/60\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:10:29Z","timestamp":1760134229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/10\/2\/60"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,28]]},"references-count":101,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["toxics10020060"],"URL":"https:\/\/doi.org\/10.3390\/toxics10020060","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,28]]}}}