{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:10:00Z","timestamp":1790961000164,"version":"4.1.0"},"reference-count":110,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Institute for Risk Assessment","award":["1328-543"],"award-info":[{"award-number":["1328-543"]}]},{"name":"Federal Institute for Risk Assessment","award":["AU 09 046:ESF\/IV-BM-B35-0005\/12"],"award-info":[{"award-number":["AU 09 046:ESF\/IV-BM-B35-0005\/12"]}]},{"name":"University of Rostock","award":["1328-543"],"award-info":[{"award-number":["1328-543"]}]},{"name":"University of Rostock","award":["AU 09 046:ESF\/IV-BM-B35-0005\/12"],"award-info":[{"award-number":["AU 09 046:ESF\/IV-BM-B35-0005\/12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo.<\/jats:p>","DOI":"10.3390\/ijms252413739","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T09:13:38Z","timestamp":1734945218000},"page":"13739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic Biomarkers of Liver Failure in Cell Models and Patient Sera: Toward Liver Damage Evaluation In Vitro"],"prefix":"10.3390","volume":"25","author":[{"given":"Simone","family":"Rentschler","sequence":"first","affiliation":[{"name":"Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Stra\u00dfe 17, 78054 VS-Schwenningen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Doss","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute IZI (Leipzig), Department Rostock, Schillingallee 68, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Stra\u00dfe 17, 78054 VS-Schwenningen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Weinschrott","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Stra\u00dfe 17, 78054 VS-Schwenningen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9514-8910","authenticated-orcid":false,"given":"Matthias","family":"Kohl","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Stra\u00dfe 17, 78054 VS-Schwenningen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7745-0152","authenticated-orcid":false,"given":"Hans-Peter","family":"Deigner","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Stra\u00dfe 17, 78054 VS-Schwenningen, Germany"},{"name":"Faculty of Science, Tuebingen University, Auf der Morgenstelle 8, 72076 T\u00fcbingen, Germany"},{"name":"Department of Anesthesiology and Intensive Care Medicine, University Hospital of Rostock, Schillingallee 35, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6221-9081","authenticated-orcid":false,"given":"Martin","family":"Sauer","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute IZI (Leipzig), Department Rostock, Schillingallee 68, 18057 Rostock, Germany"},{"name":"Department of Anesthesiology and Intensive Care Medicine, University Hospital of Rostock, Schillingallee 35, 18057 Rostock, Germany"},{"name":"Center for Anesthesiology and Intensive Care Medicine, Hospital of Magdeburg, Birkenallee 34, 39130 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jhep.2018.05.011","article-title":"Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies","volume":"69","author":"Pimpin","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"301","DOI":"10.2147\/CEG.S160537","article-title":"Liver function tests in identifying patients with liver disease","volume":"11","author":"Ahmed","year":"2018","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1016\/j.cgh.2019.07.060","article-title":"Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis","volume":"18","author":"Moon","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1021\/acs.jproteome.0c00852","article-title":"Bile Acid Profiles Are Distinct among Patients with Different Etiologies of Chronic Liver Disease","volume":"20","author":"Sang","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_5","unstructured":"Sharma, A., and Nagalli, S. (2022). Chronic Liver Disease, StatPearls Inc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1016\/S0140-6736(15)00309-8","article-title":"Acute-on-chronic liver failure","volume":"386","author":"Bernal","year":"2015","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1034\/j.1600-0676.2002.00001.x","article-title":"The pathophysiological basis of acute-on-chronic liver failure","volume":"22","author":"Sen","year":"2002","journal-title":"Liver"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0140-6736(10)60274-7","article-title":"Acute liver failure","volume":"376","author":"Bernal","year":"2010","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0140-6736(19)31894-X","article-title":"Acute liver failure","volume":"394","author":"Stravitz","year":"2019","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1056\/NEJMra1208937","article-title":"Acute Liver Failure","volume":"369","author":"Bernal","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E48","DOI":"10.1208\/aapsj080106","article-title":"Mechanisms of drug-induced liver injury","volume":"8","author":"Holt","year":"2006","journal-title":"AAPS J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2010.11.006","article-title":"Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver","volume":"54","author":"Begriche","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s40264-018-0743-2","article-title":"Drug-Induced Liver Injury: Highlights of the Recent Literature","volume":"42","author":"Real","year":"2019","journal-title":"Drug Saf."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1016\/j.fct.2011.04.034","article-title":"Effects of dietary phenolics and botanical extracts on hepatotoxicity-related endpoints in human and rat hepatoma cells and statistical models for prediction of hepatotoxicity","volume":"49","author":"Liu","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/S1462399411002110","article-title":"Molecular mechanisms underlying chemical liver injury","volume":"14","author":"Gu","year":"2012","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1002\/elps.201500095","article-title":"LC-MS untargeted metabolomic analysis of drug-induced hepatotoxicity in HepG2 cells","volume":"36","author":"Castell","year":"2015","journal-title":"Electrophoresis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1039\/C2TX20051A","article-title":"In vitro models for liver toxicity testing","volume":"2","author":"Soldatow","year":"2013","journal-title":"Toxicol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/sj.clpt.6100243","article-title":"Preclinical Predictors of Clinical Safety: Opportunities for Improvement","volume":"82","author":"Sistare","year":"2007","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/03602530601093489","article-title":"Primary Hepatocytes: Current Understanding of the Regulation of Metabolic Enzymes and Transporter Proteins, and Pharmaceutical Practice for the Use of Hepatocytes in Metabolism, Enzyme Induction, Transporter, Clearance, and Hepatotoxicity Studies","volume":"39","author":"Hewitt","year":"2007","journal-title":"Drug Metab. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cbi.2006.12.003","article-title":"The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics","volume":"168","author":"Guillouzo","year":"2007","journal-title":"Chem. Biol. Interact."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.drudis.2012.10.003","article-title":"Three-dimensional cell culture: The missing link in drug discovery","volume":"18","author":"Breslin","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.taap.2005.01.050","article-title":"Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals","volume":"207","author":"Stierum","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Erdemli, G., Ju, H., and Pereira, S. (2015). Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species. Antitargets and Drug Safety, John Wiley & Sons, Ltd.","DOI":"10.1002\/9783527673643.ch13"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/03602532.2022.2039688","article-title":"Through a glass, darkly? HepaRG and HepG2 cells as models of human phase I drug metabolism","volume":"54","author":"Stanley","year":"2022","journal-title":"Drug Metab. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pharmthera.2012.01.001","article-title":"A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity","volume":"134","author":"Astashkina","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1007\/s00204-018-2286-9","article-title":"In vitro assessment of hepatotoxicity by metabolomics: A review","volume":"92","author":"Cuykx","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/978-94-007-7696-8_46","article-title":"Biomarkers in Neonatology","volume":"Volumes 1\u20132","author":"Mussap","year":"2015","journal-title":"General Methods in Biomarker Research and Their Applications"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5426","DOI":"10.1002\/anie.200905579","article-title":"Targeted Metabolomics for Biomarker Discovery","volume":"49","author":"Griffiths","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13167-016-0074-2","article-title":"Discovery of biomarkers in rare diseases: Innovative approaches by predictive and personalized medicine","volume":"7","author":"Kohl","year":"2016","journal-title":"EPMA J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Solberg, R., Enot, D., Deigner, H.-P., Koal, T., Scholl-B\u00fcrgi, S., Saugstad, O.D., and Keller, M. (2010). Metabolomic Analyses of Plasma Reveals New Insights into Asphyxia and Resuscitation in Pigs. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009606"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.yjmcc.2012.08.025","article-title":"Using metabolomics to assess myocardial metabolism and energetics in heart failure","volume":"55","author":"Turer","year":"2013","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00204-016-1874-9","article-title":"Current limitations and future opportunities for prediction of DILI from in vitro","volume":"91","author":"Funk","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.tiv.2013.06.024","article-title":"Toxicology in Vitro 3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity studies","volume":"28","author":"Mueller","year":"2014","journal-title":"Toxicol. In Vitro"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/jat.3090","article-title":"HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening","volume":"35","author":"Wang","year":"2015","journal-title":"J. Appl. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.tibtech.2006.06.003","article-title":"How omics technologies can contribute to the \u20183R\u2019 principles by introducing new strategies in animal testing","volume":"24","author":"Kroeger","year":"2006","journal-title":"Trends Biotechnol."},{"key":"ref_36","first-page":"528","article-title":"Similarities and Differences in the Expression of Drug-Metabolizing Enzymes between Human Hepatic Cell Lines and Primary Human Hepatocytes","volume":"39","author":"Ferreira","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3109\/10408444.2012.682115","article-title":"rganotypic liver culture models: Meeting current challenges in toxicity testing","volume":"42","author":"Lecluyse","year":"2012","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.bcp.2018.06.026","article-title":"Critical differences in drug metabolic properties of human hepatic cellular models, including primary human hepatocytes, stem cell derived hepatocytes, and hepatoma cell lines","volume":"155","author":"Kvist","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1007\/s00204-015-1519-4","article-title":"Translational biomarkers of acetaminophen-induced acute liver injury","volume":"89","author":"Beger","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1177\/15353702211002153","article-title":"Qualification of translational safety biomarkers","volume":"246","author":"Sauer","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1517\/17425255.2013.827170","article-title":"The current status of biomarkers for predicting toxicity","volume":"9","author":"Campion","year":"2013","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.yrtph.2013.07.006","article-title":"Qualification of cardiac troponins for nonclinical use: A regulatory perspective","volume":"67","author":"Hausner","year":"2013","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1099-e7","DOI":"10.1097\/01.CCM.0000259462.97164.A0","article-title":"Incidence and prognosis of early hepatic dysfunction in critically ill patients\u2014A prospective multicenter study","volume":"35","author":"Kramer","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1055\/s-0042-1755274","article-title":"Management of Acute Liver Failure: Update 2022","volume":"42","author":"Tujios","year":"2022","journal-title":"Semin. Liver Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.cld.2013.07.001","article-title":"Drug-induced Acute Liver Failure","volume":"17","author":"Lee","year":"2013","journal-title":"Clin. Liver Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41572-019-0105-0","article-title":"Drug-induced liver injury","volume":"5","author":"Andrade","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_47","first-page":"748","article-title":"Pharmacogenetics of Drug-Induced Liver Injury","volume":"52","author":"Russmann","year":"2010","journal-title":"Pharmacology"},{"key":"ref_48","first-page":"1095","article-title":"Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden","volume":"40","author":"Jerlstad","year":"2009","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kuntz, E., and Kuntz, H.-D. (2008). Clinical and morphological principles. Hepatology Textbook and Atlas, Springer.","DOI":"10.1007\/978-3-540-76839-5"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1152\/physrev.1983.63.4.1420","article-title":"Carnitine\u2014metabolism and functions","volume":"63","author":"Bremer","year":"1983","journal-title":"Physiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev.pa.27.040187.001353","article-title":"The Pharmacology of Carnitine","volume":"27","author":"Bahl","year":"1987","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/BF03261931","article-title":"Carnitine and Acylcarnitines","volume":"51","author":"Reuter","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00204-013-1118-1","article-title":"Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans","volume":"88","author":"McGill","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kamei, Y., Kamei, D., Tsuchiya, K., Mineshima, M., and Nitta, K. (2018). Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201591"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0885-4505(90)90047-5","article-title":"Free carnitine and acylcarnitine levels in sera of alcoholics","volume":"44","author":"Rozas","year":"1990","journal-title":"Biochem. Med. Metab. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Miyaaki, H., Kobayashi, H., Miuma, S., Fukusima, M., Sasaki, R., Haraguchi, M., and Nakao, K. (2020). Blood carnitine profiling on tandem mass spectrometry in liver cirrhotic patients. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-01190-6"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/hep.1840030413","article-title":"Elevated Plasma Carnitine in Hepatic Cirrhosis","volume":"3","author":"Fuller","year":"2007","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1016\/j.chemosphere.2007.03.049","article-title":"Carnitine, acylcarnitine and amino acid profiles analyzed by tandem mass spectrometry in a surfactant\/virus mouse model of acute hepatic encephalopathy","volume":"68","author":"Murphy","year":"2007","journal-title":"Chemosphere"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1007\/s00204-018-2214-z","article-title":"Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures","volume":"92","author":"Rodrigues","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"E1378","DOI":"10.1152\/ajpendo.00656.2013","article-title":"Acylcarnitines activate proinflammatory signaling pathways","volume":"306","author":"Rutkowsky","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Sampey, B.P., Freemerman, A.J., Zhang, J., Kuan, P.-F., Galanko, J.A., O\u2019Connell, T.M., Ilkayeva, O.R., Muehlbauer, M.J., Stevens, R.D., and Newgard, C.B. (2012). Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038812"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.3945\/jn.108.103754","article-title":"Plasma Acylcarnitine Profiles Suggest Incomplete Long-Chain Fatty Acid \u03b2-Oxidation and Altered Tricarboxylic Acid Cycle Activity in Type 2 Diabetic African-American Women","volume":"139","author":"Adams","year":"2009","journal-title":"J. Nutr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1194\/jlr.R700019-JLR200","article-title":"Phosphatidylcholine and choline homeostasis","volume":"49","author":"Li","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S1388-1981(02)00328-1","article-title":"Phosphatidylcholine and cell death","volume":"1585","author":"Cui","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbamem.2017.04.006","article-title":"Biochimica et Biophysica Acta The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease","volume":"1859","author":"Kennelly","year":"2017","journal-title":"BBA Biomembr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1177\/0148607101025005260","article-title":"Choline Deficiency Causes Reversible Hepatic Abnormalities in Patients Receiving Parenteral Nutrition: Proof of a Human Choline Requirement: A placebo-controlled trial","volume":"25","author":"Trial","year":"2001","journal-title":"JPEN J. Parenter. Enteral Nutr."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"37798","DOI":"10.1074\/jbc.M508575200","article-title":"Phosphatidylcholine homeostasis and liver failure","volume":"280","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.toxlet.2014.01.008","article-title":"UPLC-MS-based serum metabonomics for identifying acute liver injury biomarkers in Chinese miniature pigs","volume":"225","author":"Ma","year":"2014","journal-title":"Toxicol. Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1194\/jlr.D011916","article-title":"Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo","volume":"52","author":"Pynn","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Naganuma, T., and Kihara, A. (2014). Two Modes of Regulation of the Fatty Acid Elongase ELOVL6 by the 3-Ketoacyl-CoA Reductase KAR in the Fatty Acid Elongation Cycle. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101823"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Blaess, M., Csuk, R., Sch\u00e4tzl, T., and Deigner, H.-P. (2024). Elongation of Very Long-Chain Fatty Acids (ELOVL) in Atopic Dermatitis and the Cutaneous Adverse Effect AGEP of Drugs. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179344"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Abdelmagid, S.A., Clarke, S.E., Nielsen, D.E., Badawi, A., El-Sohemy, A., Mutch, D.M., and Ma, D.W.L. (2015). Comprehensive Profiling of Plasma Fatty Acid Concentrations in Young Healthy Canadian Adults. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116195"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3945\/ajcn.113.074427","article-title":"Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation","volume":"100","author":"Zerbinati","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"14668","DOI":"10.1074\/jbc.271.25.14668","article-title":"A genetic defect in phosphatidylcholine biosynthesis triggers apoptosis in Chinese hamster ovary cells","volume":"271","author":"Cui","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.1478-3231.2007.01475.x","article-title":"Sphingolipid signalling and liver diseases","volume":"27","year":"2007","journal-title":"Liver Inl."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S0021-9258(18)52461-3","article-title":"Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation","volume":"266","author":"Kim","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1126\/science.1313189","article-title":"Tumor Necrosis Factor-\u03b1 Activates the Sphingomyelin Signal Transduction Pathway in a Cell-Free System","volume":"255","author":"Dressler","year":"1992","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/0092-8674(94)90275-5","article-title":"Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling","volume":"78","author":"Wiegmann","year":"1994","journal-title":"Cell"},{"key":"ref_79","first-page":"1","article-title":"Sphingolipid signalling: Molecular basis and role in TNF-\u03b1-induced cell death","volume":"4","author":"Tardy","year":"2002","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1126\/science.8456305","article-title":"Programmed Cell Death Induced by Ceramide","volume":"259","author":"Obeid","year":"1993","journal-title":"Science"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"C1055","DOI":"10.1152\/ajpcell.00003.2020","article-title":"The role of the sphingolipid pathway in liver fibrosis: An emerging new potential target for novel therapies","volume":"318","author":"Ishay","year":"2020","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Insausti-Urkia, N., Solsona-Vilarrasa, E., Garcia-Ruiz, C., and Fernandez-Checa, J.C. (2020). Sphingomyelinases and Liver Diseases. Biomolecules, 10.","DOI":"10.3390\/biom10111497"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s10495-007-0721-0","article-title":"Sphingolipids and cell death","volume":"12","author":"Morales","year":"2007","journal-title":"Apoptosis"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3390\/metabo3030606","article-title":"Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration","volume":"3","author":"Bhattacharyya","year":"2013","journal-title":"Metabolites"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.fct.2013.09.025","article-title":"Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice","volume":"62","author":"Lu","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1021\/tx800464q","article-title":"Serum Metabolomics Reveals Irreversible Inhibition of Fatty Acid \u03b2-Oxidation through the Suppression of PPAR\u03b1 Activation as a Contributing Mechanism of Acetaminophen-Induced Hepatotoxicity","volume":"22","author":"Chen","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"106484","DOI":"10.1016\/j.prostaglandins.2020.106484","article-title":"Sphingolipid metabolism as a marker of hepatotoxicity in drug-induced liver injury","volume":"151","author":"Li","year":"2020","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2217\/bmm.13.150","article-title":"Targeted liquid chromatography\u2013mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children","volume":"8","author":"Bhattacharyya","year":"2014","journal-title":"Biomark. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1016\/j.tiv.2013.07.010","article-title":"Baseline and genotoxic compound induced gene expression profiles in HepG2 and HepaRG compared to primary human hepatocytes","volume":"27","author":"Jetten","year":"2013","journal-title":"Toxicol. In Vitro"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"138","DOI":"10.2174\/1872312812666180709150440","article-title":"Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular Carcinoma (HEPG2\/C3A) Cell Line","volume":"12","author":"Lepri","year":"2018","journal-title":"Drug Metab. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1124\/dmd.31.8.1035","article-title":"Comparison of primary human hepatocytes and hepatoma cell lines HepG2 with regard to their biotransformation properties","volume":"31","author":"Wilkening","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/dta.3184","article-title":"HepG2 as promising cell-based model for biosynthesis of long-term metabolites: Exemplified for metandienone","volume":"14","author":"Zschiesche","year":"2022","journal-title":"Drug Test. Anal."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1002\/bit.23104","article-title":"Improvement of HepG2\/C3a cell functions in a microfluidic biochip","volume":"108","author":"Prot","year":"2011","journal-title":"Biotechnol. Bioeng."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1128\/AAC.01657-09","article-title":"Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection","volume":"54","author":"Wang","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1177\/106002809402801009","article-title":"Worsening of Liver Function with Fluconazole and Review of Azole Antifungal Hepatotoxicity","volume":"28","author":"Gearhart","year":"1994","journal-title":"Ann. Pharmacother."},{"key":"ref_96","first-page":"170","article-title":"Hepatotoxicity of antifungal agents","volume":"6","author":"Song","year":"2005","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_97","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (US) (2012). LiverTox Database\u2014Clinical and Research Information on Drug-Induced Liver Injury."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/EJA.0000000000000666","article-title":"Rocuronium is more hepatotoxic than succinylcholine in vitro","volume":"34","author":"Sauer","year":"2017","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Do\u00df, S., Potschka, H., Do\u00df, F., Mitzner, S., and Sauer, M. (2017). Hepatotoxicity of antimycotics used for invasive fungal infections: In vitro results. Biomed. Res. Int., 2017.","DOI":"10.1155\/2017\/9658018"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/toxsci\/kfx029","article-title":"Hepatocellular Toxicity of Imidazole and Triazole Antimycotic Agents","volume":"157","author":"Haegler","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/toxsci\/kfm012","article-title":"Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines","volume":"97","author":"Korashy","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.3390\/cimb46040189","article-title":"In Vitro Hepatotoxicity of Routinely Used Opioids and Sedative Drugs","volume":"46","author":"Haller","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Garc\u00eda- Ca\u00f1averas, J.C., Castell, J.V., Donato, M.T., and Lahoz, A. (2016). A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury. Sci. Rep., 6.","DOI":"10.1038\/srep27239"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1093\/bja\/aes253","article-title":"Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass","volume":"109","author":"Fechner","year":"2012","journal-title":"Br. J. Anaesth."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1086\/504492","article-title":"Pharmacology of Systemic Antifungal Agents","volume":"43","author":"Ashley","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"805","DOI":"10.4065\/mcp.2011.0247","article-title":"Current Concepts in Antifungal Pharmacology","volume":"86","author":"Lewis","year":"2011","journal-title":"Mayo Clin. Proc."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/0952-8180(94)90075-2","article-title":"Clinical pharmacology of rocuronium (ORG 9426): Study of the time course of action, dose requirement, reversibility, and pharmacokinetics","volume":"6","author":"Wierda","year":"1994","journal-title":"J. Clin. Anesth."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Kaiser, L., Weinschrott, H., Quint, I., Blaess, M., Csuk, R., Jung, M., Kohl, M., and Deigner, H.P. (2020). Metabolite patterns in human myeloid hematopoiesis result from lineage-dependent active metabolic pathways. Int. J. Mol. Sci., 21.","DOI":"10.1101\/2020.07.09.195156"},{"key":"ref_109","unstructured":"R Development Core Team (2022, November 21). A Language and Environment for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_110","unstructured":"Fox, J., and Weisberg, S. (2010). An R Companion to Applied Regression, SAGE Publications, Inc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13739\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:40Z","timestamp":1760115520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,23]]},"references-count":110,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413739"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413739","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,23]]}}}