{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T21:30:17Z","timestamp":1773696617681,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T00:00:00Z","timestamp":1591920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K08383"],"award-info":[{"award-number":["20K08383"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03562"],"award-info":[{"award-number":["19H03562"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210031"],"award-info":[{"award-number":["19fk0210031"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Mac-2 binding protein (M2BP) is a highly glycosylated secreted glycoprotein that is involved in immune defense and regulation. Our cross-sectional studies indicated that serum M2BP was a useful liver fibrosis biomarker for nonalcoholic fatty liver disease (NAFLD). In this study, we conducted a 7-year longitudinal study to investigate the significance of serum M2BP levels (baseline and at 7-year follow-up) and their relationships with other metabolic parameters of fatty liver disease. Methods: We enrolled 715 study subjects (521 male and 194 female) during health examinations. Study subjects received blood sampling tests and abdominal ultrasound tests at baseline and follow-up. Results: Univariate analyses demonstrated that serum M2BP levels were significantly correlated with various parameters related to metabolic risk (body mass index (BMI), systolic blood pressure, triglyceride, high density lipoprotein (HDL)-cholesterol) and metabolic syndrome diseases (obesity, hypertension, dyslipidemia, diabetes mellitus, fatty liver (FL)). Multiple logistic regression analyses demonstrated that BMI and FL were independent determinants for serum M2BP levels. Baseline serum M2BP levels were significant independent determinants for changes in platelet count, Fibrosis-4 (FIB4) index, and NAFLD fibrosis score. Higher serum M2BP levels (&gt;1.80 \u03bcg\/mL) strongly correlated with changes in the FIB4-index. Conclusions: The results of this study suggest that changes in serum M2BP levels reflect changes in specific metabolic disease-related parameters, and baseline serum M2BP levels could predict changes in liver fibrosis.<\/jats:p>","DOI":"10.3390\/nu12061770","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T03:17:32Z","timestamp":1592191052000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Serum Mac-2 Binding Protein Levels Associate with Metabolic Parameters and Predict Liver Fibrosis Progression in Subjects with Fatty Liver Disease: A 7-Year Longitudinal Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-902X","authenticated-orcid":false,"given":"Yoshihiro","family":"Kamada","sequence":"first","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"},{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Koseki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayu","family":"Nishida","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Asuka","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Yamada","sequence":"additional","affiliation":[{"name":"aMs NEW OTANI CLINIC, Osaka 540-0001, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1996-7740","authenticated-orcid":false,"given":"Shinji","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuo","family":"Takehara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9430-2362","authenticated-orcid":false,"given":"Eiji","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1001\/jama.287.3.356","article-title":"Prevalence of the metabolic syndrome among us adults: Findings from the third national health and nutrition examination survey","volume":"287","author":"Ford","year":"2002","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1007\/s00268-011-1013-y","article-title":"Improvement of Long-Term Outcomes in Hepatitis C Virus Antibody\u2013Positive Patients with Hepatocellular Carcinoma after Hepatectomy in the Modern Era","volume":"35","author":"Shirabe","year":"2011","journal-title":"World J. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJM199603143341104","article-title":"Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis","volume":"334","author":"Mazzaferro","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1056\/NEJM200102153440706","article-title":"Liver Biopsy","volume":"344","author":"Bravo","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_5","first-page":"s161","article-title":"Role of liver biopsy in management of chronic hepatitis C: A systematic review","volume":"36","author":"Gebo","year":"2002","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0168-8278(86)80075-7","article-title":"Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies","volume":"2","author":"Piccinino","year":"1986","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1053\/j.gastro.2005.03.084","article-title":"Sampling variability of liver biopsy in nonalcoholic fatty liver disease","volume":"128","author":"Ratziu","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver Fibrosis, but No Other Histologic Features, Is Associated with Long-term Outcomes of Patients with Nonalcoholic Fatty Liver Disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1136\/gut.2007.126417","article-title":"Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD)","volume":"56","author":"Yoneda","year":"2007","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1148\/radiol.10091662","article-title":"Nonalcoholic Fatty Liver Disease: US-based Acoustic Radiation Force Impulse Elastography","volume":"256","author":"Yoneda","year":"2010","journal-title":"Radiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.jhep.2008.02.008","article-title":"Non-invasive evaluation of liver fibrosis using transient elastography","volume":"48","author":"Castera","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/hep.21496","article-title":"The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD","volume":"45","author":"Angulo","year":"2007","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1053\/gast.2001.25540","article-title":"Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese","volume":"121","author":"Dixon","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1136\/gut.2007.146019","article-title":"A Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease","volume":"57","author":"Harrison","year":"2008","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00535-010-0305-6","article-title":"A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease","volume":"46","author":"Sumida","year":"2010","journal-title":"J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1023\/B:GLYC.0000014085.00706.d4","article-title":"90K (Mac-2 BP) and galectins in tumor progression and metastasis","volume":"19","author":"Grassadonia","year":"2002","journal-title":"Glycoconj. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.bbagen.2007.05.006","article-title":"Identification of proteins bearing \u03b21\u20136 branched N-glycans in human melanoma cell lines from different progression stages by tandem mass spectrometry analysis","volume":"1770","author":"Martuszewska","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/prca.201200137","article-title":"Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis","volume":"7","author":"Kamada","year":"2013","journal-title":"Proteom. Clin. Appl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/S0168-8278(96)80076-6","article-title":"Elevated serum levels of 90K\/MAC-2 BP predict unresponsiveness to \u03b1-interferon therapy in chronic HCV hepatitis patients","volume":"25","author":"Artini","year":"1996","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1365-2893.2009.01083.x","article-title":"The HCV serum proteome: A search for fibrosis protein markers","volume":"16","author":"Cheung","year":"2009","journal-title":"J. Viral Hepat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/hep.28002","article-title":"A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers","volume":"62","author":"Kamada","year":"2015","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/srep01065","article-title":"A serum \u201csweet-doughnut\u201d protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis","volume":"3","author":"Kuno","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s00535-014-1007-2","article-title":"Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease","volume":"50","author":"Abe","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1111\/jgh.13802","article-title":"Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: A meta-analysis","volume":"32","author":"Ito","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/liv.13188","article-title":"Serum WFA+-M2BP levels for evaluation of early stages of liver fibrosis in patients with chronic hepatitis B virus infection","volume":"37","author":"Zou","year":"2016","journal-title":"Liver Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/hepr.12595","article-title":"Impact of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein and serum interferon-?-inducible protein-10 in primary biliary cirrhosis","volume":"46","author":"Nishikawa","year":"2015","journal-title":"Hepatol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/hepr.12596","article-title":"Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis","volume":"46","author":"Nishikawa","year":"2015","journal-title":"Hepatol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/hep4.1080","article-title":"Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis","volume":"1","author":"Kamada","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1002\/hep.29631","article-title":"Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population","volume":"67","author":"Puukka","year":"2018","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1055\/s-0040-1701443","article-title":"Drinking and Obesity: Alcoholic Liver Disease\/Nonalcoholic Fatty Liver Disease Interactions","volume":"40","year":"2020","journal-title":"Semin. Liver Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Eslam, M., Newsome, P.N., Sarin, S.K., Anstee, Q.M., Targher, G., Gomez, M.R., Zelber-Sagi, S., Wong, V.W.-S., Dufour, J.-F., and Schattenberg, J.M. (2020). A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol.","DOI":"10.1016\/j.jhep.2020.03.039"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/gast.2002.35354","article-title":"The utility of radiological imaging in nonalcoholic fatty liver disease","volume":"123","author":"Saadeh","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1872-034X.2012.01066.x","article-title":"Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction: Health check-up study of Japanese men","volume":"43","author":"Hamano","year":"2012","journal-title":"Hepatol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"NASH Clinical Research Network Comparison of Noninvasive Markers of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease","volume":"7","author":"Shah","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E85","DOI":"10.4052\/tigg.1714.1E","article-title":"Mac-2 binding protein is a useful liver fibrosis biomarker for NAFLD\/NASH","volume":"29","author":"Kamada","year":"2019","journal-title":"Trends Glycosci. Glycotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1007\/s00535-011-0436-4","article-title":"Platelet count for predicting fibrosis in nonalcoholic fatty liver disease","volume":"46","author":"Yoneda","year":"2011","journal-title":"J. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sumida, Y., Yoneda, M., Hyogo, H., Itoh, Y., Ono, M., Fujii, H., Eguchi, Y., Suzuki, Y., Aoki, N., and Kanemasa, K. (2012). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol., 12.","DOI":"10.1186\/1471-230X-12-2"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"579","DOI":"10.14309\/ajg.0000000000000058","article-title":"Nonalcoholic Fatty Liver Disease","volume":"114","author":"Cheung","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jhep.2019.03.033","article-title":"Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease","volume":"71","author":"Srivastava","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/hepr.12819","article-title":"Establishment of mouse Mac-2 binding protein enzyme-linked immunosorbent assay and its application for mouse chronic liver disease models","volume":"47","author":"Iwata","year":"2016","journal-title":"Hepatol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0968-0004(94)90165-1","article-title":"The SRCR superfamily: A family reminiscent of the Ig superfamily","volume":"19","author":"Resnick","year":"1994","journal-title":"Trends Biochem. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1073\/pnas.96.6.3006","article-title":"Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo","volume":"96","author":"Trahey","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/ajg.2015.118","article-title":"Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis","volume":"110","author":"Umemura","year":"2015","journal-title":"Am. J. Gastroenterol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/6\/1770\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:38:27Z","timestamp":1760175507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/6\/1770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,12]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["nu12061770"],"URL":"https:\/\/doi.org\/10.3390\/nu12061770","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,12]]}}}