{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T02:04:34Z","timestamp":1769565874899,"version":"3.49.0"},"reference-count":123,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005297","name":"Medical University of Bia\u0142ystok","doi-asserted-by":"publisher","award":["SUB\/1\/DN\/21\/003\/1118"],"award-info":[{"award-number":["SUB\/1\/DN\/21\/003\/1118"]}],"id":[{"id":"10.13039\/501100005297","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis.<\/jats:p>","DOI":"10.3390\/ijms231911380","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T23:12:12Z","timestamp":1664320332000},"page":"11380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular Advances in MAFLD\u2014A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-3430","authenticated-orcid":false,"given":"Adrian","family":"Ko\u0142akowski","sequence":"first","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9594-6971","authenticated-orcid":false,"given":"Sylwia","family":"Dziemitko","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Chmielecka","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8470-0351","authenticated-orcid":false,"given":"Hubert","family":"\u017bywno","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1372-9445","authenticated-orcid":false,"given":"Wiktor","family":"Bzd\u0119ga","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-7476","authenticated-orcid":false,"given":"Tomasz","family":"Charytoniuk","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"},{"name":"Department of Ophthalmology, Antoni Jurasz University Hospital No. 1, 85-094 Bydgoszcz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7407-8156","authenticated-orcid":false,"given":"Adrian","family":"Chabowski","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9274-5488","authenticated-orcid":false,"given":"Karolina","family":"Konstantynowicz-Nowicka","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","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":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1111\/liv.14825","article-title":"Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018, A cost-of-illness analysis","volume":"41","author":"Schattenberg","year":"2021","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1111\/liv.14675","article-title":"MAFLD identifies patients with significant hepatic fibrosis better than NAFLD","volume":"40","author":"Yamamura","year":"2020","journal-title":"Liver Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.2147\/DMSO.S316096","article-title":"MAFLD Criteria May Overlook a Subtype of Patient with Steatohepatitis and Significant Fibrosis","volume":"14","author":"Huang","year":"2021","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ter Horst, K.W., and Serlie, M.J. (2017). Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease. Nutrients, 9.","DOI":"10.3390\/nu9090981"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1093\/ajcn\/85.6.1511","article-title":"Mechanisms for the acute effect of fructose on postprandial lipemia","volume":"85","author":"Chong","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/liv.14360","article-title":"The role of nutrition in non-alcoholic fatty liver disease: Pathophysiology and management","volume":"40","year":"2020","journal-title":"Liver Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/MCO.0000000000000539","article-title":"Omega-3 fatty acids and nonalcoholic fatty liver disease in adults and children: Where do we stand?","volume":"22","author":"Spooner","year":"2019","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14859","DOI":"10.1038\/ncomms14859","article-title":"Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice","volume":"8","author":"Schweiger","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.cell.2012.02.017","article-title":"Mechanisms for insulin resistance: Common threads and missing links","volume":"148","author":"Samuel","year":"2012","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sakurai, Y., Kubota, N., Yamauchi, T., and Kadowaki, T. (2021). Role of Insulin Resistance in MAFLD. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084156"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1124\/pr.108.00001","article-title":"Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis","volume":"60","author":"Anderson","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1053\/j.gastro.2013.11.049","article-title":"Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease","volume":"146","author":"Lambert","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.clinbiochem.2015.06.023","article-title":"Gut-liver axis, nutrition, and non-alcoholic fatty liver disease","volume":"48","author":"Kirpich","year":"2015","journal-title":"Clin. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s11154-019-09512-0","article-title":"Dietary lipids, gut microbiota and lipid metabolism","volume":"20","author":"Schoeler","year":"2019","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1177\/2050640618804444","article-title":"Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease","volume":"6","author":"Rau","year":"2018","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the gut-liver axis in NASH pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/hep.25601","article-title":"Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice","volume":"56","author":"Fuchs","year":"2012","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e855","DOI":"10.1016\/j.cgh.2020.12.033","article-title":"The Health Impact of MAFLD, a Novel Disease Cluster of NAFLD, Is Amplified by the Integrated Effect of Fatty Liver Disease-Related Genetic Variants","volume":"20","author":"Liu","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12944-020-01207-9","article-title":"Independent and joint correlation of PNPLA3 I148M and TM6SF2 E167K variants with the risk of coronary heart disease in patients with non-alcoholic fatty liver disease","volume":"19","author":"Wu","year":"2020","journal-title":"Lipids Health Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s11904-020-00531-0","article-title":"NASH in HIV","volume":"17","author":"Cervo","year":"2020","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jare.2018.12.006","article-title":"Beneficial role of bioactive lipids in the pathobiology, prevention, and management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver cirrhosis: A review","volume":"17","author":"Das","year":"2019","journal-title":"J. Adv. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, J., Fern\u00e1ndez-Galilea, M., Mart\u00ednez-Fern\u00e1ndez, L., Gonz\u00e1lez-Muniesa, P., P\u00e9rez-Ch\u00e1vez, A., Mart\u00ednez, J.A., and Moreno-Aliaga, M.J. (2019). Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation. Nutrients, 11.","DOI":"10.3390\/nu11040872"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6889533","DOI":"10.1155\/2021\/6889533","article-title":"The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD","volume":"2021","author":"Hong","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","author":"Romeo","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101111","DOI":"10.1016\/j.molmet.2020.101111","article-title":"Genetic and epigenetic factors determining NAFLD risk","volume":"50","author":"Jonas","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rajas, F., Gautier-Stein, A., and Mithieux, G. (2019). Glucose-6 Phosphate, A Central Hub for Liver Carbohydrate Metabolism. Metabolites, 9.","DOI":"10.3390\/metabo9120282"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s43152-021-00030-3","article-title":"Extracellular Matrix Remodeling in Chronic Liver Disease","volume":"2","author":"Ortiz","year":"2021","journal-title":"Curr. Tissue Microenviron Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.matbio.2017.11.011","article-title":"Matrix metalloproteinase functions in hepatic injury and fibrosis","volume":"68\u201369","author":"Roderfeld","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1002\/jcb.26622","article-title":"Three-dimensional liver-derived extracellular matrix hydrogel promotes liver organoids function","volume":"119","author":"Saheli","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.3389\/fimmu.2020.574276","article-title":"Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment","volume":"11","author":"McQuitty","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1002\/path.1397","article-title":"Liver extracellular matrix in health and disease","volume":"200","author":"Bedossa","year":"2003","journal-title":"J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2015.11.001","article-title":"Extracellular matrix structure","volume":"97","author":"Theocharis","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Naba, A., Clauser, K.R., Whittaker, C.A., Carr, S.A., Tanabe, K.K., and Hynes, R.O. (2014). Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-518"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100115","DOI":"10.1016\/j.jhepr.2020.100115","article-title":"The liver matrisome\u2013looking beyond collagens","volume":"2","author":"Arteel","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1089\/scd.2017.0095","article-title":"Decellularization of Whole Human Liver Grafts Using Controlled Perfusion for Transplantable Organ Bioscaffolds","volume":"26","author":"Verstegen","year":"2017","journal-title":"Stem Cells Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1089\/ars.2013.5697","article-title":"Extracellular matrix and liver disease","volume":"21","author":"Arriazu","year":"2014","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/liv.14390","article-title":"Collagen biology and non-invasive biomarkers of liver fibrosis","volume":"40","author":"Karsdal","year":"2020","journal-title":"Liver Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.addr.2003.08.002","article-title":"Collagens\u2014Structure, function, and biosynthesis","volume":"55","author":"Gelse","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/978-3-319-49674-0_14","article-title":"Fibrillar collagens","volume":"82","author":"Bella","year":"2017","journal-title":"Subcell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1247\/csf.26.289","article-title":"Type V collagen distribution in liver is reconstructed in coculture system of hepatocytes and stellate cells; the possible functions of type V collagen in liver under normal and pathological conditions","volume":"26","author":"Takai","year":"2001","journal-title":"Cell Struct. Funct."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1089\/ten.2006.12.519","article-title":"The basement membrane component of biologic scaffolds derived from extracellular matrix","volume":"12","author":"Brown","year":"2006","journal-title":"Tissue Eng."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/path.1437","article-title":"Functional structure and composition of the extracellular matrix","volume":"200","author":"Bosman","year":"2003","journal-title":"J. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"988","DOI":"10.4103\/1673-5374.270299","article-title":"Type XIX collagen: A promising biomarker from the basement membranes","volume":"15","author":"Calvo","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.18632\/oncotarget.2849","article-title":"Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX","volume":"6","author":"Oudart","year":"2015","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0047-6374(01)00398-0","article-title":"Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat","volume":"123","author":"Gagliano","year":"2002","journal-title":"Mech. Ageing Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"120689","DOI":"10.1016\/j.biomaterials.2021.120689","article-title":"Liver donor age affects hepatocyte function through age-dependent changes in decellularized liver matrix","volume":"270","author":"Acun","year":"2021","journal-title":"Biomaterials"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1002\/jbm.a.36460","article-title":"Fibrinogen adsorption to biomaterials","volume":"106","author":"Horbett","year":"2018","journal-title":"J. Biomed. Mater. Res.-Part A"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Halper, J., and Kjaer, M. (2014). Basic Components of Connective Tissues and Extracellular Matrix: Elastin, Fibrillin, Fibulins, Fibrinogen, Fibronectin, Laminin, Tenascins and Thrombospondins. Progress in Heritable Soft Connective Tissue Diseases, Springer.","DOI":"10.1007\/978-94-007-7893-1_3"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.3748\/wjg.v17.i20.2482","article-title":"Fibronectin: Functional character and role in alcoholic liver disease","volume":"17","author":"Casey","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/iwj.12109","article-title":"Role of fibronectin in normal wound healing","volume":"12","author":"Lenselink","year":"2015","journal-title":"Int. Wound J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.matbio.2016.07.011","article-title":"Fibronectin, the extracellular glue","volume":"60\u201361","author":"Zollinger","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.lfs.2019.04.021","article-title":"Periostin in chronic liver diseases: Current research and future perspectives","volume":"226","author":"Jia","year":"2019","journal-title":"Life Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.biomaterials.2018.07.008","article-title":"Laminin-521 promotes quiescence in isolated stellate cells from rat liver","volume":"180","author":"Rohn","year":"2018","journal-title":"Biomaterials"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1136\/gut.2009.182345","article-title":"Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver","volume":"59","author":"Lorenzini","year":"2010","journal-title":"Gut"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1136\/gutjnl-2014-308410","article-title":"Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis","volume":"64","author":"Dubuquoy","year":"2015","journal-title":"Gut"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cca.2019.01.003","article-title":"Small Leucine Rich Proteoglycans (decorin, biglycan and lumican) in cancer","volume":"491","author":"Appunni","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"G807","DOI":"10.1152\/ajpgi.00447.2014","article-title":"Novel insights into the function and dynamics of extracellular matrix in liver fibrosis","volume":"308","author":"Karsdal","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5492","DOI":"10.1074\/jbc.M111.283499","article-title":"Decorin antagonizes the angiogenic network: Concurrent inhibition of met, hypoxia inducible factor 1\u03b1, vascular endothelial growth factor A, and induction of thrombospondin-1 and tiMP3","volume":"287","author":"Neill","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"645","DOI":"10.3389\/fonc.2020.00645","article-title":"Protective Role of Decorin in Primary Hepatocellular Carcinoma","volume":"10","author":"Reszegi","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3748\/wjg.v22.i1.379","article-title":"Proteoglycans in liver cancer","volume":"22","author":"Baghy","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1136\/jim-2018-000840","article-title":"Significance of biglycan and osteopontin as non-invasive markers of liver fibrosis in patients with chronic hepatitis B virus and chronic hepatitis C virus","volume":"67","author":"Sobhy","year":"2019","journal-title":"J. Investig. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.matbio.2013.12.003","article-title":"De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88\/TRIF pathways","volume":"35","author":"Beckmann","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.semcancer.2010.05.002","article-title":"Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion","volume":"20","author":"Bourboulia","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.matbio.2015.01.004","article-title":"Matrix metalloproteinases in liver injury, repair and fibrosis","volume":"44\u201346","author":"Duarte","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Geervliet, E., and Bansal, R. (2020). Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases. Cells, 9.","DOI":"10.3390\/cells9051212"},{"key":"ref_70","first-page":"65","article-title":"Expression pattern of matrix metalloproteinases in human liver","volume":"33","author":"Lichtinghagen","year":"1995","journal-title":"Eur. J. Clin. Chem. Clin. Biochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1182\/blood.V100.4.1160.h81602001160_1160_1167","article-title":"Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo","volume":"100","author":"McQuibban","year":"2002","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s10555-006-7893-x","article-title":"Novel functions of TIMPs in cell signaling","volume":"25","author":"Chirco","year":"2006","journal-title":"Cancer Metastasis Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0163-7258(93)90074-N","article-title":"Tissue inhibitor of metalloproteinases (TIMP, aka EPA): Structure, control of expression and biological functions","volume":"59","author":"Denhardt","year":"1993","journal-title":"Pharmacol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"11069","DOI":"10.1074\/jbc.M111490200","article-title":"Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: Implications for reversibility of liver fibrosis","volume":"277","author":"Murphy","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.4049\/jimmunol.1102199","article-title":"Stromal TIMP3 regulates liver lymphocyte populations and provides protection against Th1 T cell-driven autoimmune hepatitis","volume":"188","author":"Murthy","year":"2012","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s10517-016-3338-x","article-title":"Age-Related Changes in the System Metalloproteinases\/Tissue Metalloproteinase Inhibitors and Proteoglycan Components in Mouse Organs","volume":"161","author":"Kim","year":"2016","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s12079-009-0066-2","article-title":"The matricellular functions of small leucine-rich proteoglycans (SLRPs)","volume":"3","author":"Merline","year":"2009","journal-title":"J. Cell Commun. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1161\/01.RES.0000246849.17887.66","article-title":"Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: Enhancement of VEGF biological activity by a singular growth factor\/matrix protein synergism","volume":"99","author":"Wijelath","year":"2006","journal-title":"Circ. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1002\/eji.1830271015","article-title":"Induction of T cell adhesion to extracellular matrix or endothelial cell ligands by soluble or matrix-bound interleukin-7","volume":"27","author":"Ariel","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_80","first-page":"125","article-title":"Tumour necrosis factor-alpha interacts with laminin and functions as a pro-adhesive cytokine","volume":"85","author":"Hershkoviz","year":"1995","journal-title":"Immunology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.bbadis.2012.11.002","article-title":"Extracellular matrix degradation in liver fibrosis: Biochemistry and regulation","volume":"1832","author":"Iredale","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.3390\/cancers6031220","article-title":"Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs)","volume":"6","author":"Okazaki","year":"2014","journal-title":"Cancers"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Khomich, O., Ivanov, A.V., and Bartosch, B. (2019). Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells, 9.","DOI":"10.3390\/cells9010024"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.hbpd.2018.04.003","article-title":"Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets","volume":"17","author":"Ezhilarasan","year":"2018","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1042\/EBC20180050","article-title":"Lysyl oxidases: From enzyme activity to extracellular matrix cross-links","volume":"63","author":"Vallet","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Hanson, A., Wilhelmsen, D., and DiStefano, J.K. (2018). The role of long non-coding RNAs (lncRNAs) in the development and progression of fibrosis associated with nonalcoholic fatty liver disease (NAFLD). Noncoding RNA, 4.","DOI":"10.3390\/ncrna4030018"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/his.13665","article-title":"Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease","volume":"73","author":"Munsterman","year":"2018","journal-title":"Histopathology"},{"key":"ref_88","first-page":"37","article-title":"Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis","volume":"41","author":"Barchuk","year":"2018","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.addr.2017.05.007","article-title":"Hepatic stellate cells as key target in liver fibrosis","volume":"121","author":"Higashi","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Roehlen, N., Crouchet, E., and Baumert, T.F. (2020). Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells, 9.","DOI":"10.3390\/cells9040875"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.tem.2017.03.005","article-title":"Sphingolipids and Lipoproteins in Health and Metabolic Disorders","volume":"28","author":"Iqbal","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.3389\/fimmu.2019.02893","article-title":"Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack","volume":"10","author":"Oates","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.jhep.2016.01.002","article-title":"Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease","volume":"64","author":"Luukkonen","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e0126910","DOI":"10.1371\/journal.pone.0126910","article-title":"Ceramide as a mediator of non-alcoholic Fatty liver disease and associated atherosclerosis","volume":"10","author":"Kasumov","year":"2015","journal-title":"PLoS ONE"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1111\/jgh.15005","article-title":"Effects of constant light exposure on sphingolipidomics and progression of NASH in high-fat-fed rats","volume":"35","author":"Yue","year":"2020","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/hep4.1069","article-title":"TRAIL Deletion Prevents Liver, but Not Adipose Tissue, Inflammation during Murine Diet-Induced Obesity","volume":"1","author":"Hirsova","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1194\/jlr.C066191","article-title":"Extracellular vesicles and ceramide: New mediators for macrophage chemotaxis?","volume":"57","year":"2016","journal-title":"J. Lipid. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1194\/jlr.M063412","article-title":"Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1\u03b1-dependent manner","volume":"57","author":"Kakazu","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jcmgh.2015.07.007","article-title":"Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-\u03b3","volume":"1","author":"Povero","year":"2015","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, A., Arab, J.P., Reyes, D., Lapitz, A., Moshage, H., Ba\u00f1ales, J.M., and Arrese, M. (2020). Extracellular Vesicles in NAFLD\/ALD: From Pathobiology to Therapy. Cells, 9.","DOI":"10.3390\/cells9040817"},{"key":"ref_102","first-page":"1074","article-title":"Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease","volume":"34","author":"Kurek","year":"2014","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_103","first-page":"1","article-title":"Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases","volume":"51","author":"Kim","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Zanieri, F., Levi, A., Montefusco, D., Longato, L., de Chiara, F., Frenguelli, L., Omenetti, S., Andreola, F., Luong, T.V., and Massey, V. (2020). Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH. Cells, 9.","DOI":"10.3390\/cells9051237"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S1388-1981(02)00132-4","article-title":"Sphingosine-1-phosphate and lipid phosphohydrolases","volume":"1582","author":"Peterson","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"100605","DOI":"10.1016\/j.jbc.2021.100605","article-title":"Direct uptake of sphingosine-1-phosphate independent of phospholipid phosphatases","volume":"296","author":"Goto","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1080\/10409238.2017.1337706","article-title":"Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology","volume":"52","author":"Rohrbach","year":"2017","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.3390\/molecules26113377","article-title":"Vitamin K2 as a New Modulator of the Ceramide De Novo Synthesis Pathway","volume":"26","author":"Kurzyna","year":"2021","journal-title":"Molecules"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1002\/JLB.3A0517-188RRR","article-title":"LPS and palmitate synergistically stimulate sphingosine kinase 1 and increase sphingosine 1 phosphate in RAW264.7 macrophages","volume":"104","author":"Jin","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1159\/000453213","article-title":"Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease","volume":"40","author":"Fayyaz","year":"2016","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.3389\/fimmu.2018.02980","article-title":"Hepatocyte-Derived Lipotoxic Extracellular Vesicle Sphingosine 1-Phosphate Induces Macrophage Chemotaxis","volume":"9","author":"Liao","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1194\/jlr.M063511","article-title":"SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes","volume":"56","author":"Geng","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1194\/jlr.RA120000875","article-title":"Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease","volume":"61","author":"Anderson","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"eaar5551","DOI":"10.1126\/science.aar5551","article-title":"Sphingosine 1-phosphate: Lipid signaling in pathology and therapy","volume":"366","author":"Cartier","year":"2019","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jhep.2013.02.021","article-title":"Sphingosine kinase\/sphingosine 1-phosphate (S1P)\/S1P receptor axis is involved in liver fibrosis-associated angiogenesis","volume":"59","author":"Yang","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3389\/fimmu.2020.01149","article-title":"Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome","volume":"11","author":"Hou","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.jhep.2010.08.028","article-title":"Sphingosine 1-phosphate (S1P)\/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility","volume":"54","author":"Li","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"E131","DOI":"10.1152\/ajpendo.00181.2019","article-title":"Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism","volume":"318","author":"Lu","year":"2020","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"G300","DOI":"10.1152\/ajpgi.00222.2016","article-title":"Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis","volume":"312","author":"Mauer","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1194\/jlr.M093799","article-title":"FTY720\/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice","volume":"60","author":"Rohrbach","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Becker, S., Kinny-K\u00f6ster, B., Bartels, M., Scholz, M., Seehofer, D., Berg, T., Engelmann, C., Thiery, J., Ceglarek, U., and Kaiser, T. (2017). Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174424"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e87058","DOI":"10.1172\/jci.insight.87058","article-title":"HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P(1)) promotes regeneration and suppresses fibrosis in the liver","volume":"1","author":"Ding","year":"2016","journal-title":"JCI Insight"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Hajny, S., and Christoffersen, C. (2017). A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081636"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11380\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:07Z","timestamp":1760143207000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":123,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911380"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911380","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,27]]}}}