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To investigate this, the lipidomes of liver and brain tissues from long-term high fat diet (HFD) feeding and HFD with single ethanol (EtOH) binge (HFD + EtOH) mice were characterized by comprehensive two-dimensional (2D) liquid chromatography\u2013mass spectrometry. Multiple database matching was used for high-confidence lipid identification. Univariable and multivariable analyses were employed to identify lipids with significantly altered abundance between HFD + EtOH and HFD mice. Furthermore, differential correlation analysis and cross-tissue codysregulation mapping were performed. Our data indicated that alcohol feeding induced profound tissue-specific lipidomic alterations. Triglycerides increased significantly, and phospholipids decreased in the livers of alcohol-treated mice, whereas their brains exhibited elevation of oxidized lipids with subclass-divergent changes in glycerolipids, glycerophospholipids, and sphingolipids. Differential correlation analysis revealed extensive remodeling of lipid interaction networks in the alcohol-exposed brain. Cross-tissue analysis identified 18 codysregulated lipids demonstrating a strongly correlated lipid regulation shift in HFD + EtOH mice. Collectively, alcohol rewires organ-specific lipidomes through distinct mechanisms and induces correlated multitissue lipid dysregulation, suggesting potential lipid-centric communication along the liver-brain axis. These findings provide novel insights into ALD pathogenesis and reveal potential biomarkers for multiorgan involvement.<\/jats:p>","DOI":"10.1021\/acs.jproteome.5c00916","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:05:04Z","timestamp":1785935104000},"page":"4435-4447","source":"Crossref","is-referenced-by-count":0,"title":["Integrated\nLiver and Brain Lipidomics Reveals Coordinated\nRemodeling in a High-Fat Diet Plus Binge Ethanol Mouse Model of Alcohol-Associated\nLiver Disease"],"prefix":"10.1021","volume":"25","author":[{"given":"Jing","family":"Feng","sequence":"first","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yuan","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-8961","authenticated-orcid":true,"given":"Raobo","family":"Xu","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xipeng","family":"Ma","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Gasparetto","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4023-2020","authenticated-orcid":true,"given":"Eugene","family":"Mueller","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Wayne State University , , , ,","place":["Detroit, Michigan, United States, 48201"]},{"name":"Wayne State University , , , ,","place":["Detroit, Michigan, United States, 48201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0428-814X","authenticated-orcid":true,"given":"Liqing","family":"He","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Warner","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"Robley Rex Louisville VAMC , , ,","place":["Louisville, Kentucky, United States, 40292"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Kirpich","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1102-6313","authenticated-orcid":true,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40208"]},{"name":"University of Louisville , , , ,","place":["Louisville, Kentucky, United States, 40202"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"issue":"2","key":"2026090409131876300_cit1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1007\/s10865-011-9353-5","article-title":"Co-Occurrence of Obesity and Patterns of Alcohol Use\nAssociated with Elevated Serum Hepatic Enzymes in US Adults","volume":"35","author":"Tsai","year":"2012","journal-title":"J. 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P.; Liangpunsakul, S.; Ding, W.-X.; Szabo, G.; Mehal, W.; Wang, H.; He, Y.; Sta\u0308rkel, P.; Llorente, C.; Schnabl, B.; Hwang, S.; Vandermerwe, S.; Gao, Y.; Zheng, M.-H.; Kim, W.; George, J.; Bataller, R.; Loomba, R.; Leggio, L.; Tacke, F.\n          Metabolic Dysfunction and Alcohol-Associated Liver\nDisease (MetALD)\n          eGastroenterology\n          2025; 3((4)), , 10.1136\/egastro-2025-100319.","DOI":"10.1136\/egastro-2025-100319"},{"issue":"4","key":"2026090409131876300_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2026.101749","article-title":"Management of Obesity\nin Advanced Chronic Liver Disease","volume":"8","author":"Caussy","year":"2026","journal-title":"JHEP Rep."},{"issue":"6","key":"2026090409131876300_cit5","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1002\/hep.29631","article-title":"Interaction\nbetween Alcohol Consumption and Metabolic Syndrome in\nPredicting Severe Liver Disease in the General Population","volume":"67","author":"\u00c5berg","year":"2018","journal-title":"Hepatology"},{"issue":"1","key":"2026090409131876300_cit6","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.jhep.2022.08.030","article-title":"Alcohol Consumption\nand Metabolic Syndrome: Clinical\nand Epidemiological Impact on Liver Disease","volume":"78","author":"\u00c5berg","year":"2023","journal-title":"J. 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Pharmacol."},{"key":"2026090409131876300_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2026.101460","article-title":"The Multiorgan\nCrosstalk\nNetwork of the Liver-Brain Axis: From Molecular Mechanisms to Emerging\nTherapeutic Targets","volume":"108","author":"Wang","year":"2026","journal-title":"Mol. Aspects Med."},{"key":"2026090409131876300_cit16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2021.108915","article-title":"Organ and\nBrain Crosstalk: The Liver-Brain Axis in Gastrointestinal, Liver,\nand Pancreatic Diseases","volume":"205","author":"Matsubara","year":"2022","journal-title":"Neuropharmacology"},{"issue":"1","key":"2026090409131876300_cit17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010463","article-title":"The Association between\nHepatic Encephalopathy and Diabetic Encephalopathy:\nThe Brain-Liver Axis","volume":"22","author":"Cheon","year":"2021","journal-title":"Int. J. Mol. 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Liver Physiol."},{"key":"2026090409131876300_cit21","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-026-03746-x","article-title":"Ozone-Induced Cognitive Deficits Are Mediated by the Liver\u2013Brain\nAxis: Peripheral Complement C3 Triggers Microglial Synaptic Phagocytosis","volume":"23","author":"Wang","year":"2026","journal-title":"J. Neuroinflammation"},{"issue":"6","key":"2026090409131876300_cit22","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.3803\/EnM.2021.1331","article-title":"Serotonergic\nRegulation of Hepatic Energy Metabolism","volume":"36","author":"Park","year":"2021","journal-title":"Endocrinol.\nMetab."},{"issue":"1","key":"2026090409131876300_cit23","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ejphar.2009.06.044","article-title":"Melatonin Protects\nagainst Alcoholic Liver Injury by Attenuating Oxidative Stress, Inflammatory\nResponse, and Apoptosis","volume":"616","author":"Hu","year":"2009","journal-title":"Eur. J. 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Hepatol."},{"issue":"3","key":"2026090409131876300_cit33","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nprot.2013.032","article-title":"Mouse Model\nof Chronic and Binge Ethanol Feeding (the NIAAA Model)","volume":"8","author":"Bertola","year":"2013","journal-title":"Nat. Protoc."},{"key":"2026090409131876300_cit34","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-020-00616-8","article-title":"Higher Sensitivity of Female Cells\nto Ethanol: Methylation of DNA Lowers Cyp2e1, Generating More ROS","volume":"18","author":"Penaloza","year":"2020","journal-title":"Cell Commun. Signaling"},{"issue":"5","key":"2026090409131876300_cit35","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1002\/hep.510230513","article-title":"Prediction\nof Risk\nof Liver Disease by Alcohol Intake, Sex, and Age: A Prospective Population\nStudy","volume":"23","author":"Becker","year":"1996","journal-title":"Hepatology"},{"issue":"4","key":"2026090409131876300_cit36","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1111\/acer.13346","article-title":"Liver Injury and\nEndotoxemia in Male and Female Alcohol-Dependent\nIndividuals Admitted to an Alcohol Treatment Program","volume":"41","author":"Kirpich","year":"2017","journal-title":"Alcohol.: Clin. Exp. 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