{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T15:55:09Z","timestamp":1776959709491,"version":"3.51.4"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16J10577"],"award-info":[{"award-number":["16J10577"]}],"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":["19K24330"],"award-info":[{"award-number":["19K24330"]}],"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":["20K19498"],"award-info":[{"award-number":["20K19498"]}],"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":["17H02183"],"award-info":[{"award-number":["17H02183"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Substantial evidence suggests an important role of liver function in brain health. Liver function is clinically assessed by measuring the activity of hepatic enzymes in the peripheral blood. Brain-derived neurotrophic factor (BDNF) is an important regulator of brain function. Therefore, we hypothesized that blood BDNF levels are associated with liver function and fibrosis. To test this hypothesis, in this cross-sectional study, we investigated whether serum BDNF concentration is associated with liver enzyme activity, aspartate aminotransferase (AST)\/ alanine aminotransferase (ALT) ratio, and fibrosis-4 (FIB-4) index in middle-aged and older women. We found that serum BDNF level showed a significant positive association with ALT and \u03b3-glutamyltranspeptidase (GGT) activity and negative association with FIB-4 index, and a trend of negative association with the AST\/ALT ratio after adjustment for age. Additionally, these associations remained statistically significant even after adjustment for body mass index (BMI) and fasting blood glucose level. These results demonstrate associations of serum BDNF levels with liver enzymes and hepatic fibrosis-related indices, which may underlie liver-brain interactions.<\/jats:p>","DOI":"10.1371\/journal.pone.0273056","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T17:34:22Z","timestamp":1661276062000},"page":"e0273056","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association of serum brain-derived neurotrophic factor with hepatic enzymes, AST\/ALT ratio, and FIB-4 index in middle-aged and older women"],"prefix":"10.1371","volume":"17","author":[{"given":"Takumi","family":"Yokokawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Sase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2297-1647","authenticated-orcid":true,"given":"Satoshi","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"pone.0273056.ref001","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1212\/WNL.0000000000002498","article-title":"Nonalcoholic fatty liver disease is associated with cognitive function in adults","volume":"86","author":"SW Seo","year":"2016","journal-title":"Neurology"},{"key":"pone.0273056.ref002","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1111\/liv.14161","article-title":"Non\u2010alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle\u2010aged adults: The Framingham Study","volume":"39","author":"G Weinstein","year":"2019","journal-title":"Liver Int"},{"key":"pone.0273056.ref003","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1001\/jamaneurol.2017.3229","article-title":"Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study","volume":"75","author":"G Weinstein","year":"2018","journal-title":"Jama Neurol"},{"key":"pone.0273056.ref004","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1038\/s41598-018-38357-x","article-title":"Non-alcoholic fatty liver disease and cerebral small vessel disease in Korean cognitively normal individuals","volume":"9","author":"H Jang","year":"2019","journal-title":"Sci Rep-uk"},{"key":"pone.0273056.ref005","doi-asserted-by":"crossref","first-page":"e197978","DOI":"10.1001\/jamanetworkopen.2019.7978","article-title":"Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers","volume":"2","author":"K Nho","year":"2019","journal-title":"Jama Netw Open"},{"key":"pone.0273056.ref006","doi-asserted-by":"crossref","first-page":"10827","DOI":"10.1073\/pnas.0402141101","article-title":"Essential role of brain-derived neurotrophic factor in adult hippocampal function","volume":"101","author":"LM Monteggia","year":"2004","journal-title":"P Natl Acad Sci Usa"},{"key":"pone.0273056.ref007","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.nlm.2008.07.014","article-title":"BDNF is a novel marker of cognitive function in ageing women: The DR\u2019s EXTRA Study","volume":"90","author":"P Komulainen","year":"2008","journal-title":"Neurobiol Learn Mem"},{"key":"pone.0273056.ref008","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neurobiolaging.2004.03.002","article-title":"The impact of age, weight and gender on BDNF levels in human platelets and plasma","volume":"26","author":"M Lommatzsch","year":"2005","journal-title":"Neurobiol Aging"},{"key":"pone.0273056.ref009","doi-asserted-by":"crossref","first-page":"5368","DOI":"10.1523\/JNEUROSCI.6251-09.2010","article-title":"Brain-Derived Neurotrophic Factor Is Associated with Age-Related Decline in Hippocampal Volume","volume":"30","author":"KI Erickson","year":"2010","journal-title":"J Neurosci"},{"key":"pone.0273056.ref010","first-page":"402","article-title":"TNF-\u03b1 and IL-1\u03b2 levels in dementia patients","volume":"256","author":"C Yasutake","year":"2006","journal-title":"Eur Arch Psy Clin N"},{"key":"pone.0273056.ref011","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0165-1781(02)00127-0","article-title":"Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients","volume":"110","author":"K Toyooka","year":"2002","journal-title":"Psychiat Res"},{"key":"pone.0273056.ref012","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0165-1781(02)00005-7","article-title":"Decreased serum brain-derived neurotrophic factor levels in major depressed patients","volume":"109","author":"F Karege","year":"2002","journal-title":"Psychiatry Res"},{"key":"pone.0273056.ref013","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/mp.2013.105","article-title":"Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N = 9484)","volume":"19","author":"ML Molendijk","year":"2014","journal-title":"Mol Psychiatr"},{"key":"pone.0273056.ref014","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/mp.2010.88","article-title":"Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis","volume":"16","author":"MJ Green","year":"2011","journal-title":"Mol Psychiatr"},{"key":"pone.0273056.ref015","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/mp.2016.62","article-title":"Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer\u2019s disease: a meta-analysis study (N = 7277)","volume":"22","author":"X-Y Qin","year":"2017","journal-title":"Mol Psychiatr"},{"key":"pone.0273056.ref016","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00125-006-0537-4","article-title":"Brain-derived neurotrophic factor (BDNF) and type 2 diabetes","volume":"50","author":"KS Krabbe","year":"2006","journal-title":"Diabetologia"},{"key":"pone.0273056.ref017","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev.pathmechdis.2.010506.092044","article-title":"The Aging Brain","volume":"3","author":"BA Yankner","year":"2006","journal-title":"Annu Rev Pathology Mech Dis"},{"key":"pone.0273056.ref018","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1007\/s00125-005-0023-4","article-title":"Cognitive decline and dementia in diabetes\u2014systematic overview of prospective observational studies","volume":"48","author":"T Cukierman","year":"2005","journal-title":"Diabetologia"},{"key":"pone.0273056.ref019","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00125-007-0602-7","article-title":"Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes","volume":"50","author":"SM Gold","year":"2007","journal-title":"Diabetologia"},{"key":"pone.0273056.ref020","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/sj.ijo.802225","article-title":"Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study","volume":"27","author":"MF Elias","year":"2003","journal-title":"Int J Obesity"},{"key":"pone.0273056.ref021","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/S0168-8278(00)00097-0","article-title":"Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C","volume":"34","author":"T Poynard","year":"2001","journal-title":"J Hepatol"},{"key":"pone.0273056.ref022","doi-asserted-by":"crossref","first-page":"98","DOI":"10.18632\/aging.101124","article-title":"Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling","volume":"9","author":"B Delire","year":"2016","journal-title":"Aging"},{"key":"pone.0273056.ref023","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1111\/liv.14318","article-title":"Author response: Non\u2010alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle\u2010aged adults: The Framingham study","volume":"40","author":"G Weinstein","year":"2019","journal-title":"Liver Int"},{"key":"pone.0273056.ref024","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1210\/jc.2007-2819","article-title":"Fasting Plasma Glucose Cutoff for Diagnosis of Diabetes in a Japanese Population","volume":"93","author":"Y Doi","year":"2008","journal-title":"J Clin Endocrinol Metabolism"},{"key":"pone.0273056.ref025","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/ajg.2016.453","article-title":"Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis","volume":"112","author":"S McPherson","year":"2017","journal-title":"Am J Gastroenterol"},{"key":"pone.0273056.ref026","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1111\/liv.12165","article-title":"Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease","volume":"33","author":"NA Youssef","year":"2013","journal-title":"Liver Int"},{"key":"pone.0273056.ref027","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.metabol.2018.11.014","article-title":"Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics","volume":"92","author":"SA Polyzos","year":"2018","journal-title":"Metabolism"},{"key":"pone.0273056.ref028","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.2337\/dc07-0792","article-title":"Nonalcoholic Fatty Liver Disease Is a Risk Factor for Type 2 Diabetes in Middle-Aged Japanese Men","volume":"30","author":"M Shibata","year":"2007","journal-title":"Diabetes Care"},{"key":"pone.0273056.ref029","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S1474-4422(05)70284-2","article-title":"Risk of dementia in diabetes mellitus: a systematic review","volume":"5","author":"GJ Biessels","year":"2006","journal-title":"Lancet Neurol"},{"key":"pone.0273056.ref030","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/j.1467-789X.2011.00920.x","article-title":"A review of the association between obesity and cognitive function across the lifespan: implications for novel approaches to prevention and treatment","volume":"12","author":"E Smith","year":"2011","journal-title":"Obes Rev"},{"key":"pone.0273056.ref031","doi-asserted-by":"crossref","first-page":"e0174169","DOI":"10.1371\/journal.pone.0174169","article-title":"Reduced brain activity in female patients with non-alcoholic fatty liver disease as measured by near-infrared spectroscopy","volume":"12","author":"A Takahashi","year":"2017","journal-title":"Plos One"},{"key":"pone.0273056.ref032","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1523\/JNEUROSCI.4540-10.2011","article-title":"Identification of cis-Elements and Transcription Factors Regulating Neuronal Activity-Dependent Transcription of Human BDNF Gene","volume":"31","author":"P Pruunsild","year":"2011","journal-title":"J Neurosci"},{"key":"pone.0273056.ref033","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/S0028-3908(98)00141-5","article-title":"Transport of brain-derived neurotrophic factor across the blood\u2013brain barrier","volume":"37","author":"W Pan","year":"1998","journal-title":"Neuropharmacology"},{"key":"pone.0273056.ref034","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1126\/science.aaw2622","article-title":"Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain","volume":"369","author":"AM Horowitz","year":"2020","journal-title":"Science"},{"key":"pone.0273056.ref035","doi-asserted-by":"crossref","first-page":"e1128","DOI":"10.1038\/tp.2017.95","article-title":"Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain\u2013liver axis","volume":"7","author":"B Yang","year":"2017","journal-title":"Transl Psychiat"},{"key":"pone.0273056.ref036","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.metabol.2018.06.007","article-title":"BDNF mimetic alleviates body weight gain in obese mice by enhancing mitochondrial biogenesis in skeletal muscle","volume":"87","author":"J Wood","year":"2018","journal-title":"Metabolism"},{"key":"pone.0273056.ref037","doi-asserted-by":"crossref","first-page":"588","DOI":"10.2337\/diabetes.48.3.588","article-title":"Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)\/lepr(db) mice","volume":"48","author":"JR Tonra","year":"1999","journal-title":"Diabetes"},{"key":"pone.0273056.ref038","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/BF02532343","article-title":"Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75ngfr, TrkA, TrkB, and TrkC) in the adult human peripheral nervous system and nonneural tissues","volume":"21","author":"M Yamamoto","year":"1996","journal-title":"Neurochem Res"},{"key":"pone.0273056.ref039","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jad.2014.01.009","article-title":"Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: A study of two independent cohorts","volume":"160","author":"K S\u00f6dersten","year":"2014","journal-title":"J Affect Disorders"},{"key":"pone.0273056.ref040","doi-asserted-by":"crossref","first-page":"e42676","DOI":"10.1371\/journal.pone.0042676","article-title":"Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder","volume":"7","author":"T Yoshida","year":"2012","journal-title":"Plos One"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273056","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T17:34:47Z","timestamp":1661276087000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273056"}},"subtitle":[],"editor":[{"given":"Kenji","family":"Hashimoto","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0273056","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,23]]}}}