{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T15:04:41Z","timestamp":1782831881633,"version":"3.54.5"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010371","name":"Lincoln College, University of Oxford","doi-asserted-by":"publisher","award":["MSD1920_APP-ID_1238189"],"award-info":[{"award-number":["MSD1920_APP-ID_1238189"]}],"id":[{"id":"10.13039\/100010371","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007723","name":"Oxford University Press","doi-asserted-by":"publisher","award":["MSD1920_APP-ID_1238189"],"award-info":[{"award-number":["MSD1920_APP-ID_1238189"]}],"id":[{"id":"10.13039\/501100007723","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Newton Abraham Studentship, University of Oxford","award":["MSD1920_APP-ID_1238189"],"award-info":[{"award-number":["MSD1920_APP-ID_1238189"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity.<\/jats:p>","DOI":"10.1371\/journal.pone.0261555","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T18:29:43Z","timestamp":1641493783000},"page":"e0261555","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Depressive symptoms in non-alcoholic fatty liver disease are identified by perturbed lipid and lipoprotein metabolism"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8781-7459","authenticated-orcid":true,"given":"Daniel E.","family":"Radford-Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preya J.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine M.","family":"Irvine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2072-9216","authenticated-orcid":true,"given":"Dan","family":"Siskind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Anthony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth E.","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fay","family":"Probert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"issue":"1","key":"pone.0261555.ref001","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"ZM Younossi","year":"2016","journal-title":"Hepatology"},{"issue":"6","key":"pone.0261555.ref002","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jhep.2015.11.004","article-title":"EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.","volume":"64","author":"European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O","year":"2016","journal-title":"J Hepatol"},{"issue":"10161","key":"pone.0261555.ref003","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"GS Malhi","year":"2018","journal-title":"Lancet"},{"issue":"1","key":"pone.0261555.ref004","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41380-018-0017-5","article-title":"Depression and obesity: evidence of shared biological mechanisms","volume":"24","author":"Y Milaneschi","year":"2019","journal-title":"Mol Psychiatry"},{"issue":"5","key":"pone.0261555.ref005","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.2337\/dc11-2055","article-title":"Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies","volume":"35","author":"A Pan","year":"2012","journal-title":"Diabetes Care"},{"issue":"9","key":"pone.0261555.ref006","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1002\/hep4.1541","article-title":"Nonalcoholic Fatty Liver Disease Increases the Risk of Anxiety and Depression.","volume":"4","author":"C Labenz","year":"2020","journal-title":"Hepatol Commun"},{"issue":"5","key":"pone.0261555.ref007","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/apt.15395","article-title":"Depression is associated with non-alcoholic fatty liver disease among adults in the United States","volume":"50","author":"D Kim","year":"2019","journal-title":"Aliment Pharmacol Ther"},{"issue":"8","key":"pone.0261555.ref008","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/hep4.1208","article-title":"A Pragmatic Approach Identifies a High Rate of Nonalcoholic Fatty Liver Disease With Advanced Fibrosis in Diabetes Clinics and At-Risk Populations in Primary Care.","volume":"2","author":"P Patel","year":"2018","journal-title":"Hepatol Commun"},{"issue":"11","key":"pone.0261555.ref009","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1093\/ecco-jcc\/jjy101","article-title":"Plasma Nuclear Magnetic Resonance Metabolomics Discriminates Between High and Low Endoscopic Activity and Predicts Progression in a Prospective Cohort of Patients With Ulcerative Colitis.","volume":"12","author":"F Probert","year":"2018","journal-title":"J Crohns Colitis"},{"issue":"8","key":"pone.0261555.ref010","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1021\/acs.jproteome.5b00354","article-title":"Analysis of the Human Adult Urinary Metabolome Variations with Age, Body Mass Index, and Gender by Implementing a Comprehensive Workflow for Univariate and OPLS Statistical Analyses","volume":"14","author":"EA Thevenot","year":"2015","journal-title":"J Proteome Res"},{"issue":"2","key":"pone.0261555.ref011","doi-asserted-by":"crossref","first-page":"fcab084","DOI":"10.1093\/braincomms\/fcab084","article-title":"Integrative biochemical, proteomics and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis","volume":"3","author":"F Probert","year":"2021","journal-title":"Brain Commun"},{"key":"pone.0261555.ref012","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: an open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"X Robin","year":"2011","journal-title":"BMC Bioinformatics"},{"issue":"5","key":"pone.0261555.ref013","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1373\/clinchem.2014.232918","article-title":"GlycA: A Composite Nuclear Magnetic Resonance Biomarker of Systemic Inflammation","volume":"61","author":"JD Otvos","year":"2015","journal-title":"Clin Chem"},{"issue":"5","key":"pone.0261555.ref014","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.biopsych.2019.08.016","article-title":"Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls","volume":"87","author":"M Bot","year":"2020","journal-title":"Biol Psychiatry"},{"issue":"6","key":"pone.0261555.ref015","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1194\/jlr.M002196","article-title":"Chronic social defeat stress disrupts regulation of lipid synthesis","volume":"51","author":"JC Chuang","year":"2010","journal-title":"J Lipid Res"},{"key":"pone.0261555.ref016","doi-asserted-by":"crossref","first-page":"23441","DOI":"10.1038\/srep23441","article-title":"Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression","volume":"6","author":"HM Jia","year":"2016","journal-title":"Sci Rep"},{"key":"pone.0261555.ref017","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/1471-230X-14-106","article-title":"Chronic stress induces steatohepatitis while decreases visceral fat mass in mice.","volume":"14","author":"YZ Liu","year":"2014","journal-title":"BMC Gastroenterol"},{"issue":"1","key":"pone.0261555.ref018","doi-asserted-by":"crossref","DOI":"10.4088\/JCP.20m13245","article-title":"An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.","volume":"82","author":"S Huckvale","year":"2020","journal-title":"J Clin Psychiatry"},{"key":"pone.0261555.ref019","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jad.2020.03.074","article-title":"Prospective associations between hsCRP and GlycA inflammatory biomarkers and depression: The Brazilian longitudinal study of adult health (ELSA-Brasil).","volume":"271","author":"AR Brunoni","year":"2020","journal-title":"J Affect Disord"},{"issue":"4","key":"pone.0261555.ref020","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.3390\/ijms15046184","article-title":"Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease.","volume":"15","author":"UJ Jung","year":"2014","journal-title":"Int J Mol Sci."},{"issue":"8","key":"pone.0261555.ref021","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1038\/s41380-020-0645-4","article-title":"An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder","volume":"26","author":"J Pu","year":"2021","journal-title":"Mol Psychiatry"},{"issue":"4","key":"pone.0261555.ref022","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1096\/fj.06-7495com","article-title":"Oral L-glutamine increases GABA levels in striatal tissue and extracellular fluid","volume":"21","author":"L Wang","year":"2007","journal-title":"FASEB J"},{"issue":"3","key":"pone.0261555.ref023","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1017\/neu.2015.59","article-title":"Increased serum levels of serine enantiomers in patients with depression.","volume":"28","author":"K Hashimoto","year":"2016","journal-title":"Acta Neuropsychiatr"},{"issue":"7","key":"pone.0261555.ref024","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1111\/liv.12165","article-title":"Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease","volume":"33","author":"NA Youssef","year":"2013","journal-title":"Liver Int"},{"issue":"6","key":"pone.0261555.ref025","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1111\/jgh.12897","article-title":"Non-alcoholic fatty liver disease comorbid with major depressive disorder: The pathological features and poor therapeutic efficacy","volume":"30","author":"W Tomeno","year":"2015","journal-title":"J Gastroenterol Hepatol"},{"issue":"1","key":"pone.0261555.ref026","doi-asserted-by":"crossref","first-page":"63","DOI":"10.31887\/DCNS.2018.20.1\/bpenninx","article-title":"Metabolic syndrome in psychiatric patients: overview, mechanisms, and implications.","volume":"20","author":"B Penninx","year":"2018","journal-title":"Dialogues Clin Neurosci"},{"issue":"9","key":"pone.0261555.ref027","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.cardfail.2011.04.016","article-title":"Depressive symptom trajectory predicts 1-year health-related quality of life in patients with heart failure","volume":"17","author":"RL Dekker","year":"2011","journal-title":"J Card Fail"},{"issue":"10","key":"pone.0261555.ref028","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.4088\/JCP.v67n1007","article-title":"Developing brief scales for use in clinical practice: the reliability and validity of single-item self-report measures of depression symptom severity, psychosocial impairment due to depression, and quality of life.","volume":"67","author":"M Zimmerman","year":"2006","journal-title":"J Clin Psychiatry"},{"issue":"12","key":"pone.0261555.ref029","article-title":"Human Postprandial Nutrient Metabolism and Low-Grade Inflammation: A Narrative Review.","volume":"11","author":"ECE Meessen","year":"2019","journal-title":"Nutrients"},{"issue":"3","key":"pone.0261555.ref030","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1093\/ajcn\/nqab132","article-title":"Meal-induced inflammation: postprandial insights from the Personalised REsponses to DIetary Composition Trial (PREDICT) study in 1000 participants.","volume":"114","author":"M Mazidi","year":"2021","journal-title":"Am J Clin Nutr"},{"issue":"6","key":"pone.0261555.ref031","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.genhosppsych.2010.09.010","article-title":"Association between change in depression and change in weight among women enrolled in weight loss treatment.","volume":"32","author":"GE Simon","year":"2010","journal-title":"Gen Hosp Psychiatry"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261555","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T18:30:17Z","timestamp":1641493817000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261555"}},"subtitle":[],"editor":[{"given":"Oscar","family":"Millet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0261555","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,6]]}}}