{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:25:32Z","timestamp":1760149532602,"version":"build-2065373602"},"reference-count":94,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Cardiovascular disease (CVD) is the leading cause of death globally. The underlying pathological driver of CVD is atherosclerosis. The primary risk factor for atherosclerosis is elevated low-density lipoprotein cholesterol (LDL-C). Dysregulation of cholesterol metabolism is synonymous with a rise in LDL-C. Due to the complexity of cholesterol metabolism and atherosclerosis mathematical models are routinely used to explore their non-trivial dynamics. Mathematical modelling has generated a wealth of useful biological insights, which have deepened our understanding of these processes. To date however, no model has been developed which fully captures how whole-body cholesterol metabolism intersects with atherosclerosis. The main reason for this is one of scale. Whole body cholesterol metabolism is defined by macroscale physiological processes, while atherosclerosis operates mainly at a microscale. This work describes how a model of cholesterol metabolism was combined with a model of atherosclerotic plaque formation. This new model is capable of reproducing the output from its parent models. Using the new model, we demonstrate how this system can be utilized to identify interventions that lower LDL-C and abrogate plaque formation.<\/jats:p>","DOI":"10.3390\/biology12081133","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T10:20:14Z","timestamp":1692008414000},"page":"1133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computationally Modelling Cholesterol Metabolism and Atherosclerosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Callum","family":"Davies","sequence":"first","affiliation":[{"name":"Department of Physical, Mathematical and Engineering Sciences, University of Chester, Chester CH1 4BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy E.","family":"Morgan","sequence":"additional","affiliation":[{"name":"School of Health & Sport Sciences, Liverpool Hope University, Liverpool L16 9JD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark T.","family":"Mc Auley","sequence":"additional","affiliation":[{"name":"Department of Physical, Mathematical and Engineering Sciences, University of Chester, Chester CH1 4BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nrcardio.2017.19","article-title":"Cardiovascular Disease in Africa: Epidemiological Profile and Challenges","volume":"14","author":"Keates","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1093\/eurheartj\/ehac249","article-title":"Risk Factors, Cardiovascular Disease, and Mortality in South America: A PURE Substudy","volume":"43","author":"Joseph","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41569-021-00607-3","article-title":"Epidemiology of Cardiovascular Disease in Europe","volume":"19","author":"Townsend","year":"2022","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jacasi.2021.04.007","article-title":"Epidemiological Features of Cardiovascular Disease in Asia","volume":"1","author":"Zhao","year":"2021","journal-title":"JACC Asia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41569-018-0119-4","article-title":"Epidemiology of Cardiovascular Disease in China: Current Features and Implications","volume":"16","author":"Zhao","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1161\/CIRCRESAHA.118.312669","article-title":"Sedentary Behavior, Exercise, and Cardiovascular Health","volume":"124","author":"Lavie","year":"2019","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vrablik, M., Dlouha, D., Todorovova, V., Stefler, D., and Hubacek, J.A. (2021). Genetics of Cardiovascular Disease: How Far Are We from Personalized CVD Risk Prediction and Management?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084182"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1017\/S0954422419000258","article-title":"Effects of Obesity on Cholesterol Metabolism and Its Implications for Healthy Ageing","volume":"33","year":"2020","journal-title":"Nutr. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tcm.2015.10.004","article-title":"Metabolic Syndrome Update","volume":"26","author":"Grundy","year":"2016","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1093\/ajcn\/nqx015","article-title":"International Food Group-Based Diet Quality and Risk of Coronary Heart Disease in Men and Women","volume":"107","author":"Fung","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Spence, J.D. (2019). Nutrition and Risk of Stroke. Nutrients, 11.","DOI":"10.3390\/nu11030647"},{"key":"ref_12","first-page":"1980","article-title":"Effects of Tobacco Smoking on Cardiovascular Disease","volume":"83","author":"Kondo","year":"2019","journal-title":"Circ. J. Off. J. Jpn. Circ. Soc."},{"key":"ref_13","first-page":"e14519","article-title":"The Gut Microbiome and Cardiovascular Disease","volume":"13","author":"Astudillo","year":"2021","journal-title":"Cureus"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gharipour, M., Mani, A., Amini Baghbahadorani, M., de Souza Cardoso, C.K., Jahanfar, S., Sarrafzadegan, N., de Oliveira, C., and Silveira, E.A. (2021). How Are Epigenetic Modifications Related to Cardiovascular Disease in Older Adults?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189949"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/14779072.2018.1497974","article-title":"The Current Status of Homocysteine as a Risk Factor for Cardiovascular Disease: A Mini Review","volume":"16","author":"Chrysant","year":"2018","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1161\/CIRCULATIONAHA.118.034273","article-title":"Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease","volume":"138","author":"Abdullah","year":"2018","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41573-021-00198-1","article-title":"Targeting Inflammation in Atherosclerosis\u2014From Experimental Insights to the Clinic","volume":"20","author":"Soehnlein","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1161\/ATVBAHA.119.312802","article-title":"Macrophages in Atherosclerosis Regression","volume":"40","author":"Barrett","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cca.2013.06.006","article-title":"Foam Cells in Atherosclerosis","volume":"424","author":"Yu","year":"2013","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jebari-Benslaiman, S., Galicia-Garc\u00eda, U., Larrea-Sebal, A., Olaetxea, J.R., Alloza, I., Vandenbroeck, K., Benito-Vicente, A., and Mart\u00edn, C. (2022). Pathophysiology of Atherosclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063346"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7427","DOI":"10.2174\/0929867328666210222092628","article-title":"Lipid-Lowering Therapies for Atherosclerosis: Statins, Fibrates, Ezetimibe and PCSK9 Monoclonal Antibodies","volume":"28","author":"Ali","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1161\/CIRCULATIONAHA.118.039415","article-title":"Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial","volume":"140","author":"Ouchi","year":"2019","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.atherosclerosis.2022.07.004","article-title":"Statin Therapy for the Primary Prevention of Cardiovascular Disease: Pros","volume":"356","author":"Razavi","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1001\/jama.291.23.2821","article-title":"Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction","volume":"291","author":"Chasman","year":"2004","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.pharmthera.2019.03.004","article-title":"The Emerging Concept of \u201cIndividualized Cholesterol-Lowering Therapy\u201d: A Change in Paradigm","volume":"199","author":"Stellaard","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.ygeno.2005.08.007","article-title":"Sequence Variation in NPC1L1 and Association with Improved LDL-Cholesterol Lowering in Response to Ezetimibe Treatment","volume":"86","author":"Simon","year":"2005","journal-title":"Genomics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","article-title":"Atherosclerosis","volume":"5","author":"Libby","year":"2019","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1038\/s41591-022-01936-7","article-title":"Lipid Lowering Effects of the CETP Inhibitor Obicetrapib in Combination with High-Intensity Statins: A Randomized Phase 2 Trial","volume":"28","author":"Nicholls","year":"2022","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41580-019-0190-7","article-title":"Mechanisms and Regulation of Cholesterol Homeostasis","volume":"21","author":"Luo","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s11745-015-4096-7","article-title":"Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and Its Key Regulators","volume":"51","author":"Alphonse","year":"2016","journal-title":"Lipids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41392-022-01125-5","article-title":"Regulation of Cholesterol Homeostasis in Health and Diseases: From Mechanisms to Targeted Therapeutics","volume":"7","author":"Duan","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.arr.2016.03.008","article-title":"Cholesterol Metabolism: A Review of How Ageing Disrupts the Biological Mechanisms Responsible for Its Regulation","volume":"27","author":"Morgan","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e016518","DOI":"10.1161\/JAHA.120.016518","article-title":"Effects of a Vegetarian Diet on Cardiometabolic Risk Factors, Gut Microbiota, and Plasma Metabolome in Subjects With Ischemic Heart Disease: A Randomized, Crossover Study","volume":"9","author":"Djekic","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1093\/eurheartj\/ehaa531","article-title":"Genetic Variability in the Absorption of Dietary Sterols Affects the Risk of Coronary Artery Disease","volume":"41","author":"Helgadottir","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1194\/jlr.R017855","article-title":"Mechanisms and Genetic Determinants Regulating Sterol Absorption, Circulating LDL Levels, and Sterol Elimination: Implications for Classification and Disease Risk","volume":"52","author":"Calandra","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1136\/heartjnl-2018-314253","article-title":"Sub-Optimal Cholesterol Response to Initiation of Statins and Future Risk of Cardiovascular Disease","volume":"105","author":"Akyea","year":"2019","journal-title":"Heart"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mehy.2017.05.013","article-title":"LDL-C Levels in Older People: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge","volume":"104","author":"Mooney","year":"2017","journal-title":"Med. Hypotheses"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1586\/17446651.2014.921569","article-title":"Lipid Metabolism and Hormonal Interactions: Impact on Cardiovascular Disease and Healthy Aging","volume":"9","author":"Mooney","year":"2014","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.csbj.2014.11.006","article-title":"Computationally Modeling Lipid Metabolism and Aging: A Mini-Review","volume":"13","author":"Mooney","year":"2015","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.mcna.2011.11.003","article-title":"Age as a Risk Factor","volume":"96","author":"Dhingra","year":"2012","journal-title":"Med. Clin. N. Am."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rodgers, J.L., Jones, J., Bolleddu, S.I., Vanthenapalli, S., Rodgers, L.E., Shah, K., Karia, K., and Panguluri, S.K. (2019). Cardiovascular Risks Associated with Gender and Aging. J. Cardiovasc. Dev. Dis., 6.","DOI":"10.3390\/jcdd6020019"},{"key":"ref_43","first-page":"49","article-title":"Chapter 2\u2014Molecular Mechanisms of the Vascular Responses to Hemodynamic Forces","volume":"Volume 4","author":"Ohayon","year":"2021","journal-title":"Biomechanics of Coronary Atherosclerotic Plaque"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1161\/CIRCULATIONAHA.111.021824","article-title":"Coronary Artery Wall Shear Stress Is Associated with Progression and Transformation of Atherosclerotic Plaque and Arterial Remodeling in Patients with Coronary Artery Disease","volume":"124","author":"Samady","year":"2011","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2017.05.005","article-title":"Oxidative Stress and Reactive Oxygen Species in Endothelial Dysfunction Associated with Cardiovascular and Metabolic Diseases","volume":"100","author":"Incalza","year":"2018","journal-title":"Vascul. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3945\/ajcn.113.076349","article-title":"Effects of Homocysteine Lowering with B Vitamins on Cognitive Aging: Meta-Analysis of 11 Trials with Cognitive Data on 22,000 Individuals","volume":"100","author":"Clarke","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41569-019-0227-9","article-title":"Vascular Smooth Muscle Cells in Atherosclerosis","volume":"16","author":"Basatemur","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"865827","DOI":"10.3389\/fgene.2022.865827","article-title":"The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis","volume":"13","author":"He","year":"2022","journal-title":"Front. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","article-title":"A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins","volume":"161","author":"Goldstein","year":"2015","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1017\/S0029665116002822","article-title":"Investigating Cholesterol Metabolism and Ageing Using a Systems Biology Approach","volume":"76","author":"Morgan","year":"2017","journal-title":"Proc. Nutr. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3390\/pr10010155","article-title":"Mathematical Models for Cholesterol Metabolism and Transport","volume":"10","author":"Zhang","year":"2022","journal-title":"Processes"},{"key":"ref_52","unstructured":"Marriott, B.P., Birt, D.F., Stallings, V.A., and Yates, A.A. (2020). Present Knowledge in Nutrition, Academic Press. [11th ed.]."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e1546","DOI":"10.1002\/wsbm.1546","article-title":"Modeling Cholesterol Metabolism and Atherosclerosis","volume":"14","year":"2022","journal-title":"WIREs Mech. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bcp.2013.03.021","article-title":"A Comprehensive Machine-Readable View of the Mammalian Cholesterol Biosynthesis Pathway","volume":"86","author":"Mazein","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jtbi.2017.12.023","article-title":"A Mathematical Model of the Mevalonate Cholesterol Biosynthesis Pathway","volume":"443","author":"Pool","year":"2018","journal-title":"J. Theor. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Mc Auley, M.T., Wilkinson, D.J., Jones, J.J.L., and Kirkwood, T.B.L. (2012). A Whole-Body Mathematical Model of Cholesterol Metabolism and Its Age-Associated Dysregulation. BMC Syst. Biol., 6.","DOI":"10.1186\/1752-0509-6-130"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.biosystems.2016.05.001","article-title":"Mathematically Modelling the Dynamics of Cholesterol Metabolism and Ageing","volume":"145","author":"Morgan","year":"2016","journal-title":"Biosystems"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1115\/1.2894079","article-title":"A Mathematical Model for the Receptor Mediated Cellular Regulation of the Low Density Lipoprotein Metabolism","volume":"113","author":"Yuan","year":"1991","journal-title":"J. Biomech. Eng."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Lu, J., H\u00fcbner, K., Nanjee, M.N., Brinton, E.A., and Mazer, N.A. (2014). An In-Silico Model of Lipoprotein Metabolism and Kinetics for the Evaluation of Targets and Biomarkers in the Reverse Cholesterol Transport Pathway. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003509"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jtbi.2008.11.016","article-title":"A Continuum Receptor Model of Hepatic Lipoprotein Metabolism","volume":"257","author":"Tindall","year":"2009","journal-title":"J. Theor. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1007\/s11538-008-9347-9","article-title":"Mathematical Model for Low Density Lipoprotein (LDL) Endocytosis by Hepatocytes","volume":"70","author":"Wattis","year":"2008","journal-title":"Bull. Math. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1109\/TBME.2011.2165066","article-title":"A Multiscale Model of Atherosclerotic Plaque Formation at Its Early Stage","volume":"58","year":"2011","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"041007","DOI":"10.1115\/1.4028969","article-title":"Mass Transport of Low Density Lipoprotein in Reconstructed Hemodynamic Environments of Human Carotid Arteries: The Role of Volume and Solute Flux through the Endothelium","volume":"137","author":"Kim","year":"2015","journal-title":"J. Biomech. Eng."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/bib\/bbv081","article-title":"Computational Modelling of Atherosclerosis","volume":"17","author":"Parton","year":"2016","journal-title":"Brief. Bioinform."},{"key":"ref_65","first-page":"D407","article-title":"BioModels-15 Years of Sharing Computational Models in Life Science","volume":"48","author":"Glont","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/bioinformatics\/btg015","article-title":"The Systems Biology Markup Language (SBML): A Medium for Representation and Exchange of Biochemical Network Models","volume":"19","author":"Hucka","year":"2003","journal-title":"Bioinforma. Oxf. Engl."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e9110","DOI":"10.15252\/msb.20199110","article-title":"SBML Level 3: An Extensible Format for the Exchange and Reuse of Biological Models","volume":"16","author":"Keating","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"58964","DOI":"10.1039\/C4RA09397F","article-title":"Control of Cholesterol Homeostasis by Entero-Hepatic Bile Transport\u2014The Role of Feedback Mechanisms","volume":"4","author":"Mishra","year":"2014","journal-title":"RSC Adv."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Morgan, A.E., and Mc Auley, M.T. (2020). Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms. Biology, 9.","DOI":"10.3390\/biology9100314"},{"key":"ref_70","first-page":"1360","article-title":"Evaluating Computational Models of Cholesterol Metabolism","volume":"1851","author":"Paalvast","year":"2015","journal-title":"Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1038\/s41467-022-29640-7","article-title":"A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance","volume":"13","author":"Filo","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1098\/rsfs.2011.0015","article-title":"Workflow for Generating Competing Hypothesis from Models with Parameter Uncertainty","volume":"1","author":"Compte","year":"2011","journal-title":"Interface Focus"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1093\/bioinformatics\/bty980","article-title":"New Models of Atherosclerosis and Multi-Drug Therapeutic Interventions","volume":"35","author":"Parton","year":"2019","journal-title":"Bioinforma. Oxf. Engl."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1093\/bioinformatics\/btl485","article-title":"COPASI\u2014A COmplex PAthway SImulator","volume":"22","author":"Hoops","year":"2006","journal-title":"Bioinform. Oxf. Engl."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"D689","DOI":"10.1093\/nar\/gkj092","article-title":"BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems","volume":"34","author":"Bornstein","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"20190022","DOI":"10.1515\/jib-2019-0022","article-title":"Systems Biology Graphical Notation: Process Description Language Level 1 Version 2.0","volume":"16","author":"Rougny","year":"2019","journal-title":"J. Integr. Bioinform."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nbt.1666","article-title":"The BioPAX Community Standard for Pathway Data Sharing","volume":"28","author":"Demir","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Junker, B.H., Klukas, C., and Schreiber, F. (2006). VANTED: A System for Advanced Data Analysis and Visualization in the Context of Biological Networks. BMC Bioinform., 7.","DOI":"10.1186\/1471-2105-7-109"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/MOL.0000000000000644","article-title":"Can Atherosclerosis Be Cured?","volume":"30","author":"Wilkins","year":"2019","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3945\/jn.111.157198","article-title":"Phytosterols Reduce Cholesterol Absorption by Inhibition of 27-Hydroxycholesterol Generation, Liver X Receptor \u03b1 Activation, and Expression of the Basolateral Sterol Exporter ATP-Binding Cassette A1 in Caco-2 Enterocytes","volume":"142","author":"Brauner","year":"2012","journal-title":"J. Nutr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/(SICI)1438-9312(200001)102:1<37::AID-EJLT37>3.0.CO;2-1","article-title":"Cholesterol-Lowering Effect of Plant Sterols","volume":"102","author":"Wester","year":"2000","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1093\/jn\/107.7.1139","article-title":"Effect of Plant Sterol Esters on the Absorption of Dietary Cholesterol","volume":"107","author":"Mattson","year":"1977","journal-title":"J. Nutr."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1476-511X-3-5","article-title":"Plant Sterols: Factors Affecting Their Efficacy and Safety as Functional Food Ingredients","volume":"3","author":"Berger","year":"2004","journal-title":"Lipids Health Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1161\/01.CIR.104.3.249","article-title":"Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions: A Longitudinal Study by High-Resolution, Noninvasive Magnetic Resonance Imaging","volume":"104","author":"Corti","year":"2001","journal-title":"Circulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.numecd.2009.04.001","article-title":"Plant Sterols from Rapeseed and Tall Oils: Effects on Lipids, Fat-Soluble Vitamins and Plant Sterol Concentrations","volume":"20","author":"Heggen","year":"2010","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1080\/07315724.2009.10719784","article-title":"The Effect of Adding Plant Sterols or Stanols to Statin Therapy in Hypercholesterolemic Patients: Systematic Review and Meta-Analysis","volume":"28","author":"Scholle","year":"2009","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/ajcn.81.2.380","article-title":"Direct Comparison of a Dietary Portfolio of Cholesterol-Lowering Foods with a Statin in Hypercholesterolemic Participants1\u201332","volume":"81","author":"Jenkins","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_88","first-page":"225","article-title":"Possibility of Atherosclerosis in an Arterial Bifurcation Model","volume":"1","author":"Razavi","year":"2011","journal-title":"BioImpacts BI"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"110426","DOI":"10.1016\/j.biopha.2020.110426","article-title":"Small Rodent Models of Atherosclerosis","volume":"129","author":"Zhao","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41569-020-0431-7","article-title":"Ageing and Atherosclerosis: Vascular Intrinsic and Extrinsic Factors and Potential Role of IL-6","volume":"18","author":"Tyrrell","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5287","DOI":"10.1111\/bph.14931","article-title":"Hyperlipidaemia and Cardioprotection: Animal Models for Translational Studies","volume":"177","author":"Andreadou","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejphar.2017.05.010","article-title":"Animal Models of Atherosclerosis","volume":"816","author":"Perrotta","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.1747-4949.2012.00772.x","article-title":"The Use of Animal as Models: Ethical Considerations","volume":"7","author":"Levy","year":"2012","journal-title":"Int. J. Stroke Off. J. Int. Stroke Soc."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/eci.12304","article-title":"Most Appropriate Animal Models to Study the Efficacy of Statins: A Systematic Review","volume":"44","author":"Pecoraro","year":"2014","journal-title":"Eur. J. Clin. Investig."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/8\/1133\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:33:36Z","timestamp":1760128416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/8\/1133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,14]]},"references-count":94,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["biology12081133"],"URL":"https:\/\/doi.org\/10.3390\/biology12081133","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2023,8,14]]}}}