{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:53:23Z","timestamp":1784375603656,"version":"3.55.0"},"reference-count":74,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"TNO Early Research Program \u2018Body Brain Interactions\u2019","award":["PMC13"],"award-info":[{"award-number":["PMC13"]}]},{"name":"TNO Early Research Program \u2018Body Brain Interactions\u2019","award":["PMC9"],"award-info":[{"award-number":["PMC9"]}]},{"name":"TNO research programs","award":["PMC13"],"award-info":[{"award-number":["PMC13"]}]},{"name":"TNO research programs","award":["PMC9"],"award-info":[{"award-number":["PMC9"]}]},{"name":"UK Dementia Research Institute","award":["PMC13"],"award-info":[{"award-number":["PMC13"]}]},{"name":"UK Dementia Research Institute","award":["PMC9"],"award-info":[{"award-number":["PMC9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-\/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.<\/jats:p>","DOI":"10.3390\/ijms231810736","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T23:16:36Z","timestamp":1663197396000},"page":"10736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-\/-.Leiden Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Florine","family":"Seidel","sequence":"first","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"},{"name":"Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-0149","authenticated-orcid":false,"given":"Robert","family":"Kleemann","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"van Duyvenvoorde","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"van Trigt","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanda","family":"Keijzer","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"van der Kooij","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6257-0899","authenticated-orcid":false,"given":"Cees","family":"van Kooten","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-9037","authenticated-orcid":false,"given":"Lars","family":"Verschuren","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-0897","authenticated-orcid":false,"given":"Aswin","family":"Menke","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Kiliaan","sequence":"additional","affiliation":[{"name":"Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Winter","sequence":"additional","affiliation":[{"name":"Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"},{"name":"UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2348-3490","authenticated-orcid":false,"given":"Timothy R.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"},{"name":"UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-7676","authenticated-orcid":false,"given":"B. Paul","family":"Morgan","sequence":"additional","affiliation":[{"name":"Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"},{"name":"UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3912-5428","authenticated-orcid":false,"given":"Frank","family":"Baas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-7260","authenticated-orcid":false,"given":"Kees","family":"Fluiter","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4996-943X","authenticated-orcid":false,"given":"Martine C.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"ref_1","unstructured":"(2021, October 18). Development Initiatives Global Nutrition Report 2017: Nourishing the SDGs. Available online: https:\/\/globalnutritionreport.org\/reports\/2017-global-nutrition-report\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3407306","DOI":"10.1155\/2018\/3407306","article-title":"The Impact of Obesity on the Cardiovascular System","volume":"2018","author":"Csige","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.3748\/wjg.v21.i5.1650","article-title":"Central Obesity and Nonalcoholic Fatty Liver Disease Risk after Adjusting for Body Mass Index","volume":"21","author":"Pang","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.5009\/gnl.2012.6.2.149","article-title":"NASH Is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications","volume":"6","author":"Farrell","year":"2012","journal-title":"Gut Liver"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1042\/CS20180306","article-title":"Atherosclerosis and Inflammation: Overview and Updates","volume":"132","author":"Geovanini","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nri2620","article-title":"Complement Regulators and Inhibitory Proteins","volume":"9","author":"Zipfel","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/eci.12093","article-title":"Activated Complement Factor 3 Is Associated with Liver Fat and Liver Enzymes: The CODAM Study","volume":"43","author":"Wlazlo","year":"2013","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jia, Q., Li, C., Xia, Y., Zhang, Q., Wu, H., Du, H., Liu, L., Wang, C., Shi, H., and Guo, X. (2015). Association between Complement C3 and Prevalence of Fatty Liver Disease in an Adult Population: A Cross-Sectional Study from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIHealth) Cohort Study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122026"},{"key":"ref_9","first-page":"6","article-title":"Serum Complement C3 Levels Are Associated with Nonalcoholic Fatty Liver Disease Independently of Metabolic Features in Chinese Population","volume":"6","author":"Xu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1002\/hep.23228","article-title":"Activation of the Complement System in Human Nonalcoholic Fatty Liver Disease","volume":"50","author":"Rensen","year":"2009","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1146\/annurev.immunol.23.021704.115835","article-title":"Role of C5a in Inflammatory Responses","volume":"23","author":"Guo","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/ng1599","article-title":"Complement Factor 5 Is a Quantitative Trait Gene That Modifies Liver Fibrogenesis in Mice and Humans","volume":"37","author":"Hillebrandt","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.imlet.2016.07.014","article-title":"The Complement Component C5 Promotes Liver Steatosis and Inflammation in Murine Non-Alcoholic Liver Disease Model","volume":"177","author":"Bavia","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.cca.2011.03.005","article-title":"Complement C3 and Cleavage Products in Cardiometabolic Risk","volume":"412","author":"Onat","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12975-018-0658-3","article-title":"Complement Complex C5b-9 Levels Are Associated with the Clinical Outcomes of Acute Ischemic Stroke and Carotid Plaque Stability","volume":"10","author":"Si","year":"2019","journal-title":"Transl. Stroke Res."},{"key":"ref_16","first-page":"477","article-title":"Quantitative Evaluation of the Terminal C5b-9 Complement Complex by ELISA in Human Atherosclerotic Arteries","volume":"69","author":"Niculescu","year":"1987","journal-title":"Clin. Exp. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/j.jacc.2020.02.058","article-title":"Complement C5 Protein as a Marker of Subclinical Atherosclerosis","volume":"75","author":"Jorge","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.atherosclerosis.2006.06.013","article-title":"Complement Regulation in Human Atherosclerotic Coronary Lesions. Immunohistochemical Evidence That C4b-Binding Protein Negatively Regulates the Classical Complement Pathway, and That C5b-9 Is Formed via the Alternative Complement Pathway","volume":"192","author":"Oksjoki","year":"2007","journal-title":"Atherosclerosis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1385\/IR:30:1:073","article-title":"The Role of Complement Activation in Atherosclerosis","volume":"30","author":"Niculescu","year":"2004","journal-title":"Immunol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12026-015-8669-6","article-title":"The Role of Complement Activation in Atherogenesis: The First 40 Years","volume":"64","author":"Vlaicu","year":"2016","journal-title":"Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1161\/01.ATV.18.11.1790","article-title":"Complement C6 Deficiency Protects against Diet-Induced Atherosclerosis in Rabbits","volume":"18","author":"Schmiedt","year":"1998","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1161\/ATVBAHA.108.169912","article-title":"Brief Report: Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Lacking the Membrane-Bound Complement Regulator CD59","volume":"28","author":"Yun","year":"2008","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.molimm.2009.10.035","article-title":"The Membrane Attack Complex of Complement Drives the Progression of Atherosclerosis in Apolipoprotein E Knockout Mice","volume":"47","author":"Lewis","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"56060","DOI":"10.18632\/oncotarget.11180","article-title":"Overexpression of Complement Component C5a Accelerates the Development of Atherosclerosis in ApoE-Knockout Mice","volume":"7","author":"An","year":"2016","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1161\/CIRCULATIONAHA.110.954370","article-title":"C5a Receptor Targeting in Neointima Formation after Arterial Injury in Atherosclerosis-Prone Mice","volume":"122","author":"Shagdarsuren","year":"2010","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcvm.2021.731315","article-title":"Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice","volume":"8","author":"Dai","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.atherosclerosis.2014.03.004","article-title":"Targeted Mouse Complement Inhibitor CR2-Crry Protects against the Development of Atherosclerosis in Mice","volume":"234","author":"Liu","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1096\/fj.10-174284","article-title":"Complement C5a Inhibition Reduces Atherosclerosis in ApoE \u2013\/\u2013 Mice","volume":"25","author":"Manthey","year":"2011","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1161\/CIRCRESAHA.108.191361","article-title":"Complement Regulator Cd59 Protects against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex","volume":"104","author":"Wu","year":"2009","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/imm.13228","article-title":"Characterizing the Original Anti-C5 Function-Blocking Antibody, BB5.1, for Species Specificity, Mode of Action and Interactions with C5","volume":"161","author":"Zelek","year":"2020","journal-title":"Immunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11629","DOI":"10.3390\/ijms222111629","article-title":"Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases","volume":"22","author":"Guti","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Van den Hoek, A.M., Verschuren, L., Worms, N., van Nieuwkoop, A., de Ruiter, C., Attema, J., Menke, A.L., Caspers, M.P.M., Radhakrishnan, S., and Salic, K. (2020). A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology. Cells, 9.","DOI":"10.3390\/cells9092014"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/hep4.1270","article-title":"Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr-\/-.Leiden Mice","volume":"2","author":"Morrison","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jhep.2017.10.031","article-title":"Preclinical Models of Non-Alcoholic Fatty Liver Disease","volume":"68","author":"Santhekadur","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3389\/fphys.2018.00132","article-title":"Key Inflammatory Processes in Human NASH Are Reflected in Ldlr\u2212\/\u2212.Leiden Mice: A Translational Gene Profiling Study","volume":"9","author":"Morrison","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_36","first-page":"83","article-title":"Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model","volume":"5","author":"Verschuren","year":"2017","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Arranz, I., Bruzzone, C., Noureddin, M., Gil-Redondo, R., Minchol\u00e9, I., Bizkarguenaga, M., Arretxe, E., Iruarrizaga-Lejarreta, M., Fern\u00e1ndez-Ramos, D., and Lopitz-Otsoa, F. (2022). Metabolic Subtypes of Patients with NAFLD Exhibit Distinctive Cardiovascular Risk Profiles. Hepatology.","DOI":"10.1002\/hep.32427"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1007\/s12072-020-10081-7","article-title":"The Role of Neutrophils in Innate Immunity-Driven Nonalcoholic Steatohepatitis: Lessons Learned and Future Promise","volume":"14","author":"Wu","year":"2020","journal-title":"Hepatol. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-2362.2004.01273.x","article-title":"C5a Delays Apoptosis of Human Neutrophils via an Extracellular Signal-Regulated Kinase and Bad-Mediated Signalling Pathway","volume":"34","author":"Perianayagam","year":"2004","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/joim.13380","article-title":"Inflammatory and Fibrotic Mechanisms in NAFLD\u2014Implications for New Treatment Strategies","volume":"291","author":"Lee","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/hep4.1479","article-title":"Pathogenesis of Nonalcoholic Steatohepatitis: An Overview","volume":"4","author":"Parthasarathy","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1097\/WNR.0b013e32834901d9","article-title":"The Effect of Complement C5a on Mitochondrial Functions of PC12 Cells","volume":"22","author":"Martinus","year":"2011","journal-title":"Neuroreport"},{"key":"ref_43","first-page":"2903","article-title":"The Complement Membrane Attack Complex Triggers Intracellular Ca2+ Fluxes Leading to NLRP3 Inflammasome Activation","volume":"126","author":"Triantafilou","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/hep.26226","article-title":"Mitochondrial Adaptations and Dysfunctions in Nonalcoholic Fatty Liver Disease","volume":"58","author":"Begriche","year":"2013","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1016\/j.molimm.2009.02.009","article-title":"CD59 but Not DAF Deficiency Accelerates Atherosclerosis in Female ApoE Knockout Mice","volume":"46","author":"An","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1006\/bbrc.2001.5276","article-title":"ApoE\u2212\/\u2212 Mice Develop Atherosclerosis in the Absence of Complement Component C5","volume":"286","author":"Patel","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41591-018-0336-8","article-title":"ApoE Attenuates Unresolvable Inflammation by Complex Formation with Activated C1q","volume":"25","author":"Yin","year":"2019","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ji, E., and Lee, S. (2021). Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115770"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5245308","DOI":"10.1155\/2020\/5245308","article-title":"Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis","volume":"2020","author":"Khatana","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcvm.2021.824481","article-title":"Oxidized Lipids: Common Immunogenic Drivers of Non-Alcoholic Fatty Liver Disease and Atherosclerosis","volume":"8","author":"Hoebinger","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_51","first-page":"2019","article-title":"Sublytic Concentrations of the Membrane Attack Complex of Complement Induce Endothelial Interleukin-8 and Monocyte Chemoattractant Protein-1 through Nuclear Factor-\u039aB Activation","volume":"150","author":"Kilgore","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/j.1538-7836.2010.04172.x","article-title":"Complement in Atherosclerosis: Friend or Foe?","volume":"9","author":"Speidl","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2019.00666","article-title":"Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis","volume":"10","author":"Flynn","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1161\/01.CIR.0000089190.95415.9F","article-title":"New Markers of Inflammation and Endothelial Cell Activation Part I","volume":"108","author":"Szmitko","year":"2003","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"29355","DOI":"10.1074\/jbc.R200003200","article-title":"Cytokine and Cytokine Receptor Pleiotropy and Redundancy","volume":"277","author":"Ozaki","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1161\/CIRCRESAHA.109.199166","article-title":"MIF Deficiency Reduces Chronic Inflammation in White Adipose Tissue and Impairs the Development of Insulin Resistance, Glucose Intolerance, and Associated Atherosclerotic Disease","volume":"105","author":"Verschuren","year":"2009","journal-title":"Circ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1161\/01.CIR.0000012942.49244.82","article-title":"Expression of Macrophage Migration Inhibitory Factor in Different Stages of Human Atherosclerosis","volume":"105","author":"Goebel","year":"2002","journal-title":"Circulation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nm1567","article-title":"MIF Is a Noncognate Ligand of CXC Chemokine Receptors in Inflammatory and Atherogenic Cell Recruitment","volume":"13","author":"Bernhagen","year":"2007","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1161\/01.CIR.0000134704.84454.D2","article-title":"Macrophage Migration Inhibitory Factor Deficiency Impairs Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice","volume":"109","author":"Pan","year":"2004","journal-title":"Circulation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.1053\/j.gastro.2015.05.012","article-title":"Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis","volume":"149","author":"Sendler","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.atherosclerosis.2009.05.021","article-title":"Induction of MIF Expression by Oxidized LDL via Activation of NF-\u039aB in Vascular Smooth Muscle Cells","volume":"207","author":"Chen","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gart, E., Salic, K., Morrison, M.C., Caspers, M., van Duyvenvoorde, W., Heijnk, M., Giera, M., Bobeldijk-Pastorova, I., Keijer, J., and Storsve, A.B. (2021). Krill Oil Treatment Increases Distinct Pufas and Oxylipins in Adipose Tissue and Liver and Attenuates Obesity-Associated Inflammation via Direct and Indirect Mechanisms. Nutrients, 13.","DOI":"10.3390\/nu13082836"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jim.2015.02.010","article-title":"Functional Assessment of Mouse Complement Pathway Activities and Quantification of C3b\/C3c\/IC3b in an Experimental Model of Mouse Renal Ischaemia\/Reperfusion Injury","volume":"419","author":"Kotimaa","year":"2015","journal-title":"J. Immunol. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.atherosclerosis.2016.05.001","article-title":"Resolvin E1 Attenuates Atherosclerosis in Absence of Cholesterol-Lowering Effects and on Top of Atorvastatin","volume":"250","author":"Salic","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., Lindeman, J.H., Stoop, R., Havekes, L.M., Kleemann, R., and Van Den Hoek,  A.M. (2014). Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Morrison, M.C., Mulder, P., Stavro, P.M., Su\u00e1rez, M., Arola-Arnal, A., Van Duyvenvoorde, W., Kooistra, T., Wielinga, P.Y., and Kleemann, R. (2015). Replacement of Dietary Saturated Fat by PUFA-Rich Pumpkin Seed Oil Attenuates Non-Alcoholic Fatty Liver Disease and Atherosclerosis Development, with Additional Health Effects of Virgin over Refined Oil. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139196"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Schoemaker, M.H., Kleemann, R., Morrison, M.C., Verheij, J., Salic, K., Van Tol, E.A.F., Kooistra, T., and Wielinga, P.Y. (2017). A Casein Hydrolysate Based Formulation Attenuates Obesity and Associated Nonalcoholic Fatty Liver Disease and Atherosclerosis in LDLr-\/-.Leiden Mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180648"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1161\/01.CIR.89.5.2462","article-title":"AHA Medical \/ Scientific Statement Special Report A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis","volume":"89","author":"Stary","year":"1994","journal-title":"Circulation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1161\/01.ATV.15.9.1512","article-title":"A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis","volume":"15","author":"Stary","year":"1995","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Salic, K., Gart, E., Seidel, F., Verschuren, L., Caspers, M., van Duyvenvoorde, W., Wong, K.E., Keijer, J., Bobeldijk-Pastorova, I., and Wielinga, P.Y. (2019). Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184359"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"601160","DOI":"10.3389\/fendo.2021.601160","article-title":"Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine","volume":"12","author":"Mueller","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal Analysis Approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"154873","DOI":"10.1016\/j.metabol.2021.154873","article-title":"Diet and Exercise Reduce Pre-Existing NASH and Fibrosis and Have Additional Beneficial Effects on the Vasculature, Adipose Tissue and Skeletal Muscle via Organ-Crosstalk","volume":"124","author":"Worms","year":"2021","journal-title":"Metabolism"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10736\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:31:39Z","timestamp":1760142699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10736"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,14]]},"references-count":74,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810736"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810736","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,14]]}}}