{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:37:25Z","timestamp":1784633845261,"version":"3.55.0"},"reference-count":108,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Georgia Clinical & Translational Science Alliance of the National Institutes of Health","award":["UL1TR002378"],"award-info":[{"award-number":["UL1TR002378"]}]},{"name":"Clemson University Genomics and Bioinformatics Facility","award":["P20GM109094"],"award-info":[{"award-number":["P20GM109094"]}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R15ES017321"],"award-info":[{"award-number":["R15ES017321"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM121342"],"award-info":[{"award-number":["P20GM121342"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Emory Integrated Metabolics and Lipidomics Core"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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 <jats:italic>in vivo<\/jats:italic>, 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 &gt; PPAR with qPCR suggesting PPAR\u03b3 signaling is more likely than PPAR\u03b1 signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b\u2019s. 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0277053","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T18:53:00Z","timestamp":1671130380000},"page":"e0277053","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity"],"prefix":"10.1371","volume":"17","author":[{"given":"Melissa M.","family":"Heintz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmine A.","family":"Eccles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1743-8116","authenticated-orcid":true,"given":"Emily M.","family":"Olack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristal M.","family":"Maner-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Ortlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9491-3403","authenticated-orcid":true,"given":"William S.","family":"Baldwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"pone.0277053.ref001","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/nyas.12016","article-title":"Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals","volume":"128","author":"HC Masuoka","year":"2013","journal-title":"Ann N Y Acad Sci"},{"key":"pone.0277053.ref002","first-page":"360","article-title":"Prevalence of obesity and severe obesity among adults: United States, 2017\u20132018","author":"CM Hales","year":"2020","journal-title":"NCHS Data Brief"},{"key":"pone.0277053.ref003","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1124\/dmd.119.087940","article-title":"A comparative analysis of cytochrome P450 activities in paired liver and small intestinal samples from patients with obesity","volume":"48","author":"V Krogstad","year":"2020","journal-title":"Drug Metab Dispos"},{"issue":"44","key":"pone.0277053.ref004","doi-asserted-by":"crossref","first-page":"18831","DOI":"10.1073\/pnas.0909731106","article-title":"Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease","volume":"106","author":"B Dong","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref005","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1042\/BJ20080740","article-title":"Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway","volume":"417","author":"RD Finn","year":"2009","journal-title":"Biochem J"},{"key":"pone.0277053.ref006","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1124\/dmd.107.019729","article-title":"Forkhead box A2-mediated regulation of female-predominant expression of the mouse Cyp2b9 gene","volume":"36","author":"T Hashita","year":"2008","journal-title":"Drug Metab Dispos"},{"key":"pone.0277053.ref007","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature03047","article-title":"Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes","volume":"432","author":"C Wolfrum","year":"2004","journal-title":"Nature"},{"key":"pone.0277053.ref008","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12263-015-0469-z","article-title":"Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice","volume":"10","author":"EF Hoek-van den Hil","year":"2015","journal-title":"Genes Nutr"},{"issue":"20","key":"pone.0277053.ref009","doi-asserted-by":"crossref","first-page":"10446","DOI":"10.1074\/jbc.M115.711028","article-title":"Persistent chromatin modifications induced by a high fat diet","volume":"291","author":"A Leung","year":"2016","journal-title":"J Biol Chem"},{"key":"pone.0277053.ref010","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jnutbio.2019.05.004","article-title":"Cyp2b-null male mice are susceptible to diet-induced obesity and perturbations in lipid homeostasis","volume":"70","author":"MM Heintz","year":"2019","journal-title":"J Nutr Biochem"},{"key":"pone.0277053.ref011","doi-asserted-by":"crossref","first-page":"7122738","DOI":"10.1155\/2022\/7122738","article-title":"Age- and diet-dependent changes in hepatic lipidomic profiles of phospholipids in male mice: Age acceleration in Cyp2b-null mice.","volume":"2022","author":"MM Heintz","year":"2022","journal-title":"J Lipids"},{"issue":"9","key":"pone.0277053.ref012","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/lipd.12095","article-title":"Cyp2b-knockdown mice poorly metabolize corn oil and are age-dependent obese","volume":"53","author":"B Damiri","year":"2018","journal-title":"Lipids"},{"issue":"2","key":"pone.0277053.ref013","first-page":"81","article-title":"Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation","volume":"7","author":"JP Hernandez","year":"2009","journal-title":"Curr Pharmacog Pers Med"},{"issue":"6806","key":"pone.0277053.ref014","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/35038112","article-title":"The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism","volume":"407","author":"P Wei","year":"2000","journal-title":"Nature"},{"issue":"3","key":"pone.0277053.ref015","doi-asserted-by":"crossref","first-page":"e0150587","DOI":"10.1371\/journal.pone.0150587","article-title":"Transcriptional Regulation of CYP2B6 Expression by Hepatocyte Nuclear Factor 3\u03b2","volume":"11","author":"L Li","year":"2016","journal-title":"Human Liver Cells. PLoS ONE"},{"issue":"37","key":"pone.0277053.ref016","doi-asserted-by":"crossref","first-page":"28457","DOI":"10.1074\/jbc.M110.118364","article-title":"CCAT\/Enhancer-binding protein a (C\/EBPa) and hepatocyte nuclear factor 4a (HNF4a) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene: Application to the development of a metabolically competent human hepatic cell model","volume":"285","author":"M Benet","year":"2010","journal-title":"J Biol Chem"},{"issue":"8","key":"pone.0277053.ref017","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1210\/me.2004-0129","article-title":"Sexually dimorphic P450 gene expression in liver-specific hepatocyte nuclear factor 4a-deficient mice","volume":"18","author":"CA Wiwi","year":"2004","journal-title":"Mol Endocrinol"},{"issue":"3","key":"pone.0277053.ref018","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1124\/dmd.108.022772","article-title":"Dexamethasone induction of murine CYP2B genes requires the glucocorticoid receptor","volume":"37","author":"E Audet-Walsh","year":"2009","journal-title":"Drug Metab Dispos"},{"issue":"2","key":"pone.0277053.ref019","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/toxsci\/kfr240","article-title":"Tissue distribution and gender-divergent expression of 78 cytochrome P450 mRNAs in mice","volume":"124","author":"HJ Renaud","year":"2011","journal-title":"Toxicol Sci"},{"key":"pone.0277053.ref020","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1124\/jpet.103.054866","article-title":"Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (Constitutive androstane receptor) expression.","volume":"307","author":"V Lamba","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"issue":"1","key":"pone.0277053.ref021","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"UM Zanger","year":"2013","journal-title":"Pharmacol Ther"},{"issue":"7","key":"pone.0277053.ref022","doi-asserted-by":"crossref","first-page":"730","DOI":"10.2174\/138920009789895534","article-title":"Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6","volume":"10","author":"SL Mo","year":"2009","journal-title":"Curr Drug Metab"},{"key":"pone.0277053.ref023","first-page":"1201","article-title":"Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse, and rat liver microsomes","volume":"9","author":"J Tang","year":"2001","journal-title":"Drug metabolism and disposition: the biological fate of a chemicals"},{"key":"pone.0277053.ref024","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.pharmthera.2006.10.002","article-title":"The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals","volume":"113","author":"E Hodgson","year":"2007","journal-title":"Pharmacol Ther"},{"issue":"2","key":"pone.0277053.ref025","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1124\/dmd.106.012427","article-title":"Human hepatic cytochrome P450-specific metabolism of parathion and chlorpyrifos","volume":"35","author":"RJ Foxenberg","year":"2007","journal-title":"Drug Metab Dispos"},{"key":"pone.0277053.ref026","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1007\/s00204-016-1893-6","article-title":"Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells","volume":"91","author":"Y Wu","year":"2016","journal-title":"Arch Toxicol"},{"key":"pone.0277053.ref027","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1007\/s00204-016-1888-3","article-title":"Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid","volume":"91","author":"T Abe","year":"2017","journal-title":"Arch Toxicol"},{"issue":"9340","key":"pone.0277053.ref028","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0140-6736(02)11203-7","article-title":"Clinical importance of the cytochromes P450","volume":"360","author":"DW Nebert","year":"2002","journal-title":"Lancet"},{"issue":"3","key":"pone.0277053.ref029","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.taap.2007.08.009","article-title":"DHA down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes by attenuating CAR translocation","volume":"225","author":"C-C Li","year":"2007","journal-title":"Toxicol Appl Pharmacol"},{"issue":"1","key":"pone.0277053.ref030","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.abb.2004.11.023","article-title":"Evidence that cytochrome P450 CYP2B19 is the major source of epoxyeicosatrienoic acids in mouse skin","volume":"435","author":"L Du","year":"2005","journal-title":"Arch Biochem Biophys"},{"issue":"15","key":"pone.0277053.ref031","doi-asserted-by":"crossref","first-page":"9279","DOI":"10.1074\/jbc.273.15.9279","article-title":"A Keratinocyte-specific epoxygenase, CYP2B12, metabolizes arachidonic acid with unusual selectivity, producing a single major epoxyeicosatrienoic acid","volume":"273","author":"DS Keeney","year":"1998","journal-title":"J Biol Chem"},{"issue":"19","key":"pone.0277053.ref032","doi-asserted-by":"crossref","first-page":"10865","DOI":"10.1016\/S0021-9258(19)38526-6","article-title":"Cytochrome P-450 enzyme-specific control of the regio- and enantiofacial selectivity of the microsomal arachidonic acid epoxygenase","volume":"265","author":"JH Capdevila","year":"1990","journal-title":"J Biol Chem"},{"issue":"5","key":"pone.0277053.ref033","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1124\/dmd.110.036707","article-title":"Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6","volume":"39","author":"C Sridar","year":"2011","journal-title":"Drug Metab Dispos"},{"key":"pone.0277053.ref034","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1124\/mol.108.053439","article-title":"A cytochrome P450-derived epoxygenated metabolite of anandamide is a potent cannabinoid receptor 2-selective agonist","volume":"75","author":"NT Snider","year":"2009","journal-title":"Mol Pharmacol"},{"issue":"3","key":"pone.0277053.ref035","doi-asserted-by":"crossref","first-page":"e0229896","DOI":"10.1371\/journal.pone.0229896","article-title":"Gender differences in diet-induced steatotic disease in Cyp2b-null mice.","volume":"15","author":"MM Heintz","year":"2020","journal-title":"PLoS ONE"},{"key":"pone.0277053.ref036","doi-asserted-by":"crossref","first-page":"108013","DOI":"10.1016\/j.dib.2022.108013","article-title":"Dataset of Endo- and Xenobiotic Inhibition of CYP2B6: Comparison to CYP3A4.","volume":"41","author":"EM Olack","year":"2022","journal-title":"Data Brief"},{"key":"pone.0277053.ref037","doi-asserted-by":"crossref","first-page":"112175","DOI":"10.1016\/j.fct.2021.112175","article-title":"Increased toxicity and retention of perflouroctane sulfonate (PFOS) in humanized CYP2B6-transgenic mice compared to Cyp2b-null mice is relieved by a high-fat diet (HFD)","volume":"152","author":"MC Hamilton","year":"2021","journal-title":"Food Chem Toxicol"},{"key":"pone.0277053.ref038","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.chemosphere.2017.09.107","article-title":"RNA sequencing indicates that atrazine induces multiple detoxification genes in Daphnia magna and this is a potential sources of its mixtures interactions with other chemicals","volume":"189","author":"AM Schmidt","year":"2017","journal-title":"Chemosphere"},{"key":"pone.0277053.ref039","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/toxsci\/kfn206","article-title":"A concentration addition model for the activation of the constitutive androstane receptor by xenobiotic mixtures","volume":"107","author":"WS Baldwin","year":"2009","journal-title":"Toxicol Sci"},{"key":"pone.0277053.ref040","doi-asserted-by":"crossref","first-page":"22080","DOI":"10.1073\/pnas.2003877117","article-title":"Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine","volume":"117","author":"MC Tillman","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref041","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1053\/j.gastro.2020.03.010","article-title":"Lactococcus lactis Subspecies cremoris Elicits Protection Against Metabolic Changes Induced by a Western-Style Diet","volume":"159","author":"CR Naudin","year":"2020","journal-title":"Gastroenterology"},{"issue":"6","key":"pone.0277053.ref042","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1124\/dmd.112.044826","article-title":"Generation and characterization of a CYP2A13\/2B6\/2F1-transgenic mouse model","volume":"40","author":"Y Wei","year":"2012","journal-title":"Drug Metabolism and Disposition"},{"issue":"3","key":"pone.0277053.ref043","doi-asserted-by":"crossref","first-page":"e0174355","DOI":"10.1371\/journal.pone.0174355","article-title":"Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9\/10\/13-null mice","volume":"12","author":"R Kumar","year":"2017","journal-title":"PloS one."},{"key":"pone.0277053.ref044","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1242\/dmm.006239","article-title":"Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice","volume":"3","author":"JE Ayala","year":"2010","journal-title":"Dis Model Mech"},{"key":"pone.0277053.ref045","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.cbi.2018.05.001","article-title":"High fat diet induced obesity is mitigated in Cyp3a-null female mice","volume":"289","author":"R Kumar","year":"2018","journal-title":"Chem-Biol Interact"},{"key":"pone.0277053.ref046","first-page":"14.0.1","article-title":"Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis.","volume":"55","author":"J Xia","year":"2016","journal-title":"Curr Protoc Bioinformatics"},{"issue":"1","key":"pone.0277053.ref047","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","volume":"45","author":"L. Breiman","year":"2001","journal-title":"Random Forests. Machine Learning"},{"key":"pone.0277053.ref048","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nmeth.3252","article-title":"Orchestrating high-throughput genomic analysis with Bioconductor","volume":"12","author":"W Huber","year":"2015","journal-title":"Nat Methods"},{"issue":"9","key":"pone.0277053.ref049","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1186\/gb-2007-8-9-r183","article-title":"The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists","volume":"8","author":"Sherman BT Huang dW","year":"2007","journal-title":"Genome Biol"},{"issue":"4","key":"pone.0277053.ref050","doi-asserted-by":"crossref","first-page":"e1007800","DOI":"10.1371\/journal.pcbi.1007800","article-title":"MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data","volume":"16","author":"A. Roopra","year":"2020","journal-title":"PLoS Comp Biol"},{"key":"pone.0277053.ref051","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"MV Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pone.0277053.ref052","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.marenvres.2003.11.001","article-title":"Differential gene expression in mummichogs (Fundulus heteroclitus) following treatment with pyrene: comparison to a creosote contaminated site","volume":"57","author":"JA Roling","year":"2004","journal-title":"Mar Environ Res"},{"key":"pone.0277053.ref053","first-page":"1372","article-title":"Processing of gene expression data generated by quantitative real-time RT-PCR","volume":"32","author":"PY Muller","year":"2002","journal-title":"Biotechniques"},{"key":"pone.0277053.ref054","article-title":"P2X7 Receptor as a Key Player in Oxidative Stress-Driven Cell Fate in Nonalcoholic Steatohepatitis.","author":"S Chatterjee","year":"2015","journal-title":"Ox Med Cell Long"},{"issue":"3","key":"pone.0277053.ref055","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/MOL.0b013e3282ff5e55","article-title":"Hepatic triglyceride synthesis and nonalcoholic fatty liver disease","volume":"19","author":"SS Choi","year":"2008","journal-title":"Curr Opin Lipid"},{"key":"pone.0277053.ref056","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3389\/fphys.2019.00423","article-title":"Circadian Clock Genes in the Metabolism of Non-alcoholic Fatty Liver Disease.","volume":"10","author":"D Shi","year":"2019","journal-title":"Front Physiol"},{"key":"pone.0277053.ref057","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fendo.2018.00169","article-title":"ANGPTL8: An Important Regulator in Metabolic Disorders","volume":"9","author":"M Luo","year":"2018","journal-title":"Front Endocrinol"},{"issue":"274","key":"pone.0277053.ref058","doi-asserted-by":"crossref","first-page":"ra31","DOI":"10.1126\/scisignal.2003705","article-title":"Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling","volume":"6","author":"S Mutoh","year":"2013","journal-title":"Sci Signal"},{"issue":"20","key":"pone.0277053.ref059","doi-asserted-by":"crossref","first-page":"9079","DOI":"10.1128\/MCB.24.20.9079-9091.2004","article-title":"Gigu\u00e8re V, Kelly DP. Estrogen-Related Receptor \u03b1 Directs Peroxisome Proliferator-Activated Receptor \u03b1 Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle","volume":"24","author":"JM Huss","year":"2004","journal-title":"Mol Cell Biol"},{"key":"pone.0277053.ref060","doi-asserted-by":"crossref","first-page":"6042162","DOI":"10.1155\/2016\/6042162","article-title":"PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes","volume":"2016","author":"L Fang","year":"2016","journal-title":"PPAR Res."},{"key":"pone.0277053.ref061","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.cmet.2006.08.005","article-title":"Lipin 1 is an inducible amplifier of the hepatic PGC-1a\/PPARa regulatory pathway","volume":"4","author":"BN Finck","year":"2006","journal-title":"Cell Metab"},{"issue":"23","key":"pone.0277053.ref062","doi-asserted-by":"crossref","first-page":"10508","DOI":"10.1073\/pnas.1000788107","article-title":"A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation","volume":"107","author":"M Kawai","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"issue":"19","key":"pone.0277053.ref063","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.7150\/thno.28676","article-title":"Small heterodimer partner regulates circadian cytochromes P450 and drug-induced hepatotoxicity.","volume":"8","author":"T Zhang","year":"2018","journal-title":"Theranostics"},{"key":"pone.0277053.ref064","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.bcp.2007.05.027","article-title":"13-oxo-ODE is an endogenous ligand for PPARg in human colonic epithelial cells","volume":"74","author":"R Altmann","year":"2007","journal-title":"Biochem Pharmacol"},{"issue":"6","key":"pone.0277053.ref065","doi-asserted-by":"crossref","first-page":"E1195","DOI":"10.1152\/ajpendo.00513.2004","article-title":"PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes","volume":"288","author":"SE Schadinger","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"8","key":"pone.0277053.ref066","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1096\/fj.10-173716","article-title":"Role for PPAR\u03b3 in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts","volume":"25","author":"E Mor\u00e1n-Salvador","year":"2011","journal-title":"FASEB J"},{"key":"pone.0277053.ref067","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1194\/jlr.M700002-JLR200","article-title":"P450 CYP2C epoxygenase and CYP4A w-hydroxylase mediate ciprofibrate-induced PPARa-dependent peroxisomal proliferation","volume":"48","author":"A Gatica","year":"2007","journal-title":"J Lipid Res"},{"key":"pone.0277053.ref068","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1055\/s-0036-1597248","article-title":"Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin","volume":"36","author":"JF Ge","year":"2016","journal-title":"Semin Liver Dis"},{"issue":"12","key":"pone.0277053.ref069","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1002\/jcb.24247","article-title":"Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells","volume":"113","author":"S-Y Jung","year":"2012","journal-title":"J Cell Biochem"},{"key":"pone.0277053.ref070","doi-asserted-by":"crossref","first-page":"13101","DOI":"10.1038\/s41598-017-13298-z","article-title":"MCT1 and MCT4 expression and lactate flux activity increase during white and brown adipogenesis and impact adipocyte metabolism","volume":"7","author":"C Petersen","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0277053.ref071","doi-asserted-by":"crossref","first-page":"E9499","DOI":"10.1073\/pnas.1806635115","article-title":"ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism","volume":"115","author":"Z Huang","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref072","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.bbrc.2012.07.038","article-title":"a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels","volume":"424","author":"Zhang R. Lipasin","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0277053.ref073","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-015-0324-y","article-title":"Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study.","volume":"15","author":"HS Chung","year":"2016","journal-title":"Cardiovasc Diabetol"},{"issue":"7472","key":"pone.0277053.ref074","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nature12710","article-title":"A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use","volume":"502","author":"S Liu","year":"2013","journal-title":"Nature"},{"key":"pone.0277053.ref075","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1073\/pnas.0130116100","article-title":"Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis","volume":"100","author":"D Yabe","year":"2003","journal-title":"Proc Nat Acad Sci USA"},{"key":"pone.0277053.ref076","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1517\/13543784.2013.778971","article-title":"Therapeutic potential of serum and glucocorticoid inducible kinase inhibition","volume":"22","author":"F Lang","year":"2013","journal-title":"Exp Opin Investig Drugs"},{"issue":"11","key":"pone.0277053.ref077","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.3390\/nu12113476","article-title":"Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm","volume":"12","author":"K Duszka","year":"2020","journal-title":"Nutrients"},{"key":"pone.0277053.ref078","doi-asserted-by":"crossref","first-page":"9958","DOI":"10.1038\/s41598-017-10523-7","article-title":"PPAR\u03b1-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting","volume":"7","author":"J-H Lee","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0277053.ref079","volume":"2014","author":"L Chen","year":"2014","journal-title":"PPARs Integrate the Mammalian Clock and Energy Metabolism PPAR Res"},{"key":"pone.0277053.ref080","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ejphar.2014.01.045","article-title":"EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells","volume":"727","author":"J-x Jiang","year":"2014","journal-title":"Eur J Pharmacol"},{"key":"pone.0277053.ref081","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00011-019-01231-1","article-title":"Bobi\u0144ski R, Dutka M. Self\u2010regulation of the inflammatory response by peroxisome proliferator\u2010activated receptors","volume":"68","author":"J Korbecki","year":"2019","journal-title":"Inflammation Res"},{"key":"pone.0277053.ref082","first-page":"106","article-title":"Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia","author":"AM Patwardhan","year":"2009","journal-title":"Proc Nat Acad Sci USA"},{"issue":"5","key":"pone.0277053.ref083","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1177\/2042018818759894","article-title":"9- and 13-HODE regulate fatty acid binding protein-4 in human macrophages, but does not involve HODE\/GPR132 axis in PPAR-\u03b3 regulation of FABP4","volume":"9","author":"V Vangaveti","year":"2018","journal-title":"Ther Adv Endocrinol Metab"},{"issue":"12","key":"pone.0277053.ref084","doi-asserted-by":"crossref","first-page":"8400","DOI":"10.1073\/pnas.122196999","article-title":"An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors","volume":"99","author":"SM Huang","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref085","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/ng790","article-title":"JunB can substitute for Jun in mouse development and cell proliferation","volume":"30","author":"E Passegu\u00e9","year":"2002","journal-title":"Nature Genetics"},{"key":"pone.0277053.ref086","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1186\/1471-2407-11-484","article-title":"Role and expression of FRS2 and FRS3 in prostate cancer","volume":"11","author":"T Valencia","year":"2011","journal-title":"BMC Cancer"},{"key":"pone.0277053.ref087","doi-asserted-by":"crossref","first-page":"116","DOI":"10.15252\/embj.201695027","article-title":"Aryl hydrocarbon receptor is required for optimal B-cell proliferation","volume":"36","author":"M Villa","year":"2017","journal-title":"EMBO J"},{"key":"pone.0277053.ref088","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1016\/j.ajpath.2011.08.014","article-title":"Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in AxB Mice","volume":"179","author":"IN Hines","year":"2011","journal-title":"Am J Pathol"},{"issue":"1","key":"pone.0277053.ref089","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1530\/JOE-19-0275","article-title":"SGK1 activation exacerbates diet-induced obesity, metabolic syndrome and hypertension","volume":"244","author":"C Sierra-Ramos","year":"2020","journal-title":"J Endocrinol"},{"key":"pone.0277053.ref090","doi-asserted-by":"crossref","first-page":"144707","DOI":"10.1016\/j.gene.2020.144707","article-title":"ANGPTL8 enhances insulin sensitivity by directly activating insulin-mediated AKT phosphorylation","volume":"749","author":"Z Zhang","year":"2020","journal-title":"Gene"},{"key":"pone.0277053.ref091","doi-asserted-by":"crossref","first-page":"112863","DOI":"10.1016\/j.jep.2020.112863","article-title":"Agriophyllum oligosaccharides ameliorate hepatic injury in type 2 diabetic db\/db mice targeting INS-R\/IRS-2\/PI3K\/AKT\/PPAR-\u03b3\/Glut4 signal pathway","volume":"257","author":"S Bao","year":"2020","journal-title":"J Ethnopharmacol"},{"issue":"9","key":"pone.0277053.ref092","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/nsmb.1474","article-title":"Structural basis for the activation of PPARg by oxidized fatty acids","volume":"15","author":"T Itoh","year":"2008","journal-title":"Nat Struc Mol Biol"},{"issue":"8","key":"pone.0277053.ref093","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/sj.onc.1209160","article-title":"Oxidative metabolism of linoleic acid modulates PPAR-beta\/delta suppression of PPAR-gamma activity","volume":"25","author":"X Zuo","year":"2006","journal-title":"Oncogene"},{"key":"pone.0277053.ref094","doi-asserted-by":"crossref","first-page":"31649","DOI":"10.1038\/srep31649","article-title":"15-Lipoxygenase metabolites of \u03b1-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome","volume":"6","author":"N Kumar","year":"2016","journal-title":"Sci Rep"},{"issue":"2","key":"pone.0277053.ref095","first-page":"477","article-title":"Effects of the antirheumatic remedy hox alpha\u2014a new stinging nettle leaf extract\u2014on matrix metalloproteinases in human chondrocytes in vitro","volume":"17","author":"G Schulze-Tanzil","year":"2002","journal-title":"Histol Histopathol"},{"key":"pone.0277053.ref096","article-title":"Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis","author":"X Zhang","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref097","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1104\/pp.109.146282","article-title":"Soybean oil: genetic approaches for modification of functionality and total content","volume":"151","author":"TE Clemente","year":"2009","journal-title":"Plant Physiol"},{"key":"pone.0277053.ref098","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jhep.2011.05.019","article-title":"Lipotoxicity in NASH.","volume":"56","author":"M Fuchs","year":"2012","journal-title":"J Hepatol"},{"key":"pone.0277053.ref099","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cld.2009.07.009","article-title":"Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis","volume":"13","author":"K. Cusi","year":"2009","journal-title":"Clin Liver Dis"},{"key":"pone.0277053.ref100","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.taap.2014.05.009","article-title":"Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes","volume":"279","author":"C Lynch","year":"2014","journal-title":"Toxicol Appl Pharmacol"},{"key":"pone.0277053.ref101","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1007\/s00125-017-4260-0","article-title":"Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans","volume":"60","author":"MH Gangadhariah","year":"2017","journal-title":"Diabetologia"},{"key":"pone.0277053.ref102","doi-asserted-by":"crossref","first-page":"12488","DOI":"10.1038\/s41598-017-12624-9","article-title":"Omega-6 and omega-3 oxylipins are implicated in soybean oil induced obesity in mice.","volume":"7","author":"P Deol","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0277053.ref103","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1002\/hep.20920","article-title":"Insulin resistance: A metabolic pathway to chronic liver disease","volume":"42","author":"E Bugianesi","year":"2005","journal-title":"Hepatology"},{"key":"pone.0277053.ref104","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.numecd.2010.05.003","article-title":"Relationship between fatty liver and glucose metabolism: A cross-sectional study in 571 obese children","volume":"22","author":"G Bedogni","year":"2012","journal-title":"Nutr Metab Cardiovas Dis"},{"key":"pone.0277053.ref105","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.1073\/pnas.0408452102","article-title":"Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice","volume":"102","author":"A Xu","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0277053.ref106","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.2337\/db06-0097","article-title":"A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet","volume":"55","author":"PJ Raubenheimer","year":"2006","journal-title":"Diabetes"},{"key":"pone.0277053.ref107","doi-asserted-by":"crossref","first-page":"818945","DOI":"10.1155\/2009\/818945","article-title":"Cross-talk between PPARg and insulin signaling and modulation of insulin sensitivity.","volume":"2009","author":"A Leonardini","year":"2009","journal-title":"PPAR Res"},{"issue":"4","key":"pone.0277053.ref108","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.livres.2018.12.001","article-title":"Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2.","volume":"2","author":"YK Lee","year":"2018","journal-title":"Liver Res."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277053","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T18:54:20Z","timestamp":1671130460000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277053"}},"subtitle":[],"editor":[{"given":"Nobuyuki","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":108,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277053","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]}}}