{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:07:17Z","timestamp":1791256037841,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007214","name":"Velux Stiftung","doi-asserted-by":"publisher","award":["1156"],"award-info":[{"award-number":["1156"]}],"id":[{"id":"10.13039\/100007214","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Non\u2010alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45\u201365) individuals (<jats:italic>N<\/jats:italic>\u2009=\u2009496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite\u2013HTGC associations, based on univariate results, was created using correlation\u2010based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB\u20104) index were tested using a closed global test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analyses revealed that 118 metabolites were univariately associated with HTGC (<jats:italic>p<\/jats:italic>\u2010value &lt;6.59\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>), including 106 endogenous, 1 xenobiotic and 11 partially characterized\/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl\u2010ceramide and lactosyl\u2010ceramide. We also identified a novel possible HTGC\u2010related pathway connecting glutamate, metabolonic lactone sulphate and X\u201015245 using the GGM network. These pathways were confirmed to be associated with the FIB\u20104 index as well. The full interactive metabolite\u2010HTGC atlas is provided online: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/tofaquih.github.io\/AtlasLiver\/\">https:\/\/tofaquih.github.io\/AtlasLiver\/<\/jats:ext-link>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB\u20104 index. Moreover, we report a novel pathway glutamate\u2010metabolonic lactone sulphate\u2010X\u201015245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis\u2010related outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15575","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T13:53:43Z","timestamp":1680702823000},"page":"1458-1472","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hepatic triglyceride content is intricately associated with numerous metabolites and biochemical pathways"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8026-2251","authenticated-orcid":false,"given":"Tariq O.","family":"Faquih","sequence":"first","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Bert","family":"van Klinken","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"},{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"},{"name":"Department of Pediatrics, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifang","family":"Li\u2010Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the Netherlands"},{"name":"Metabolon, Inc.  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Noordam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Gerontology and Geriatrics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"van Heemst","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Gerontology and Geriatrics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Boone","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Sheridan","sequence":"additional","affiliation":[{"name":"Metabolon, Inc.  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Michelotti","sequence":"additional","affiliation":[{"name":"Metabolon, Inc.  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildo","family":"Lamb","sequence":"additional","affiliation":[{"name":"Department of Radiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e","family":"de Mutsert","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits R.","family":"Rosendaal","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"van Hylckama\u00a0Vlieg","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden the 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