{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:31:31Z","timestamp":1790785891748,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union","award":["FP7-HEALTH n 305707"],"award-info":[{"award-number":["FP7-HEALTH n 305707"]}]},{"name":"European Union","award":["FP7-603091"],"award-info":[{"award-number":["FP7-603091"]}]},{"name":"European Union","award":["2015T068"],"award-info":[{"award-number":["2015T068"]}]},{"name":"European Union","award":["2009T038"],"award-info":[{"award-number":["2009T038"]}]},{"name":"CVON","award":["FP7-HEALTH n 305707"],"award-info":[{"award-number":["FP7-HEALTH n 305707"]}]},{"name":"CVON","award":["FP7-603091"],"award-info":[{"award-number":["FP7-603091"]}]},{"name":"CVON","award":["2015T068"],"award-info":[{"award-number":["2015T068"]}]},{"name":"CVON","award":["2009T038"],"award-info":[{"award-number":["2009T038"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.<\/jats:p>","DOI":"10.3390\/nu14224936","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T03:08:37Z","timestamp":1669086517000},"page":"4936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1648-9851","authenticated-orcid":false,"given":"Yared","family":"Paalvast","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enchen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1812-7694","authenticated-orcid":false,"given":"Yvonne J. W.","family":"Rozendaal","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-0458","authenticated-orcid":false,"given":"Yanan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Gerding","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo H.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-3291","authenticated-orcid":false,"given":"Jan Freark","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":false,"given":"Patrick C. N.","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"},{"name":"Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2172-7394","authenticated-orcid":false,"given":"Ko Willems","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"},{"name":"Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Kuivenhoven","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-4730","authenticated-orcid":false,"given":"Natal A. W.","family":"van Riel","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands"},{"name":"Laboratory of Experimental Vascular Medicine, University of Amsterdam, Amsterdam UMC, Meibergdreef, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert K.","family":"Groen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"},{"name":"Laboratory of Experimental Vascular Medicine, University of Amsterdam, Amsterdam UMC, Meibergdreef, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18B","DOI":"10.1016\/S0002-9149(98)00033-2","article-title":"Hypertriglyceridemia, Atherogenic Dyslipidemia, and the Metabolic Syndrome","volume":"81","author":"Grundy","year":"1998","journal-title":"Am. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature14177","article-title":"Genetic studies of body mass index yield new insights for obesity biology","volume":"518","author":"Locke","year":"2015","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13376","DOI":"10.14814\/phy2.13376","article-title":"Male apoE*3-Leiden.CETP mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men","volume":"5","author":"Paalvast","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1161\/01.ATV.0000243925.65265.3c","article-title":"Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclero-sis in APOE*3-Leiden mice","volume":"26","author":"Westerterp","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tiemann, C.A., Vanlier, J., Hilbers, P.A., and van Riel, N.A. (2011). Parameter adaptations during phenotype transitions in progressive diseases. BMC Syst. Biol., 5.","DOI":"10.1186\/1752-0509-5-174"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rozendaal, Y.J.W., Wang, Y., Paalvast, Y., Tambyrajah, L.L., Li, Z., Van Dijk, K.W., Rensen, P.C.N., Kuivenhoven, J.A., Groen, A.K., and Hilbers, P.A.J. (2018). In vivo and in silico dynamics of the development of Metabolic Syndrome. PLOS Comput. Biol., 14.","DOI":"10.1371\/journal.pcbi.1006145"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tiemann, C.A., Vanlier, J., Oosterveer, M.H., Groen, A.K., Hilbers, P.A.J., and van Riel, N.A.W. (2013). Parameter Trajectory Analysis to Identify Treatment Effects of Pharmacological Interventions. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003166"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1161\/CIRCRESAHA.114.300632","article-title":"Regulation of High-Density Lipoprotein Metabolism","volume":"114","author":"Rye","year":"2014","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1194\/jlr.M022194","article-title":"Trans-intestinal cholesterol efflux is not mediated through high density lipo-protein","volume":"53","author":"Vrins","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19211","DOI":"10.1074\/jbc.M109.014860","article-title":"Faculty Opinions recommendation of Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol","volume":"284","author":"Vrins","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0021-9258(18)57092-7","article-title":"Method for the determination of fat in feces","volume":"177","author":"Huinink","year":"1949","journal-title":"J. Biol. Chem."},{"key":"ref_12","first-page":"642","article-title":"Studies on the site of the feedback control of cholesterol synthesis","volume":"39","author":"Siperstein","year":"1960","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0022-2275(20)38331-0","article-title":"Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions","volume":"30","author":"Heuman","year":"1989","journal-title":"J. Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"G494","DOI":"10.1152\/ajpgi.00156.2003","article-title":"Feeding natural hydrophilic bile acids inhibits intestinal choles-terol absorption: Studies in the gallstone-susceptible mouse","volume":"285","author":"Wang","year":"2003","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1096\/fj.201701084RR","article-title":"Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice","volume":"32","author":"Chevre","year":"2018","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1136\/gutjnl-2019-319693","article-title":"Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice","volume":"69","author":"Higuchi","year":"2020","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e3471","DOI":"10.1002\/cnm.3471","article-title":"Combining data assimilation and machine learning to build data-driven models for unknown long time dynamics\u2014Applications in cardiovascular modeling","volume":"37","author":"Regazzoni","year":"2021","journal-title":"Int. J. Numer. Methods Biomed. Eng."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"536957","DOI":"10.3389\/fbioe.2020.536957","article-title":"Metabolic Modeling Combined with Machine Learning Integrates Longitudinal Data and Identifies the Origin of LXR-Induced Hepatic Steatosis","volume":"8","author":"Tiemann","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_19","first-page":"G602","article-title":"Phenotypical heterogeneity in responder and nonresponder male ApoE*3Leiden.CETP mice","volume":"315","author":"Tarasco","year":"2018","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2337\/db09-1471","article-title":"A recurring problem with the analysis of energy expenditure in genetic models express-ing lean and obese phenotypes","volume":"59","author":"Butler","year":"2010","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R459","DOI":"10.1152\/ajpregu.00137.2012","article-title":"Indirect calorimetry in laboratory mice and rats: Principles, practical considerations, interpretation and perspectives","volume":"303","author":"Even","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25474","DOI":"10.1074\/jbc.M202013200","article-title":"DGAT1 Is Not Essential for Intestinal Triacylglycerol Absorption or Chylomicron Synthesis","volume":"277","author":"Buhman","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1007\/s11695-013-1166-x","article-title":"The effect of bari-atric surgery on intestinal absorption and transit time","volume":"24","author":"Carswell","year":"2014","journal-title":"Obes. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev-physiol-021115-105439","article-title":"Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium","volume":"78","author":"Gribble","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"382","DOI":"10.4161\/gmic.25723","article-title":"Cirrhosis, bile acids and gut microbiota: Unraveling a complex relationship","volume":"4","author":"Ridlon","year":"2013","journal-title":"Gut Microbes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1159\/000371678","article-title":"Gut Microbiota, Cirrhosis, and Alcohol Regulate Bile Acid Metabolism in the Gut","volume":"33","author":"Ridlon","year":"2015","journal-title":"Dig. Dis."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/22\/4936\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:59Z","timestamp":1760145779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/22\/4936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":26,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["nu14224936"],"URL":"https:\/\/doi.org\/10.3390\/nu14224936","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}