{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:56:55Z","timestamp":1791385015271,"version":"4.3.3"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003382","name":"Core Research for Evolutional Science and Technology","doi-asserted-by":"publisher","award":["16gm0610001h0205"],"award-info":[{"award-number":["16gm0610001h0205"]}],"id":[{"id":"10.13039\/501100003382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26870066"],"award-info":[{"award-number":["26870066"]}],"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":["17K15919"],"award-info":[{"award-number":["17K15919"]}],"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>Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis.<\/jats:p>","DOI":"10.1371\/journal.pone.0249556","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T22:34:25Z","timestamp":1618439665000},"page":"e0249556","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Intrahepatic distribution of nerve fibers and alterations due to fibrosis in diseased liver"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1756-7228","authenticated-orcid":true,"given":"Kei","family":"Mizuno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Haga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Okumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Hoshikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Katsumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taketo","family":"Nishina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5623-4250","authenticated-orcid":true,"given":"Yoshiyuki","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"issue":"5","key":"pone.0249556.ref001","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/nrgastro.2012.32","article-title":"The enteric nervous system and neurogastroenterology","volume":"9","author":"JB Furness","year":"2012","journal-title":"Nature reviews Gastroenterology & hepatology"},{"issue":"2","key":"pone.0249556.ref002","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/cphy.c120018","article-title":"Hepatic nervous system and neurobiology of the liver","volume":"3","author":"KJ Jensen","year":"2013","journal-title":"Comprehensive Physiology"},{"issue":"3","key":"pone.0249556.ref003","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/BF01005057","article-title":"Cholinergic nerves in the human liver","volume":"13","author":"F Amenta","year":"1981","journal-title":"The Histochemical journal"},{"issue":"6","key":"pone.0249556.ref004","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1177\/030006059602400603","article-title":"Demonstration of noradrenaline-immunoreactive nerve fibres in the liver","volume":"24","author":"Y Fukuda","year":"1996","journal-title":"The Journal of international medical research"},{"issue":"2","key":"pone.0249556.ref005","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jss.2014.12.006","article-title":"Liver innervation and hepatic function: new insights.","volume":"194","author":"AN Kandilis","year":"2015","journal-title":"The Journal of surgical research"},{"issue":"4","key":"pone.0249556.ref006","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.bbadis.2010.01.006","article-title":"The role of the autonomic nervous liver innervation in the control of energy metabolism","volume":"1802","author":"CX Yi","year":"2010","journal-title":"Biochimica et biophysica acta"},{"key":"pone.0249556.ref007","doi-asserted-by":"crossref","first-page":"7940","DOI":"10.1038\/ncomms8940","article-title":"A hepatic amino acid\/mTOR\/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals","volume":"6","author":"K Uno","year":"2015","journal-title":"Nature communications"},{"issue":"2","key":"pone.0249556.ref008","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/hepr.12760","article-title":"Autonomic Nervous System and the Liver","volume":"47","author":"K Mizuno","year":"2017","journal-title":"Hepatology research: the official journal of the Japan Society of Hepatology"},{"issue":"3","key":"pone.0249556.ref009","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/01.RES.72.3.552","article-title":"Hepatorenal reflex plays an important role in natriuresis after high-NaCl food intake in conscious dogs","volume":"72","author":"H Morita","year":"1993","journal-title":"Circulation research"},{"key":"pone.0249556.ref010","doi-asserted-by":"crossref","first-page":"21481","DOI":"10.1038\/srep21481","article-title":"Autonomic nervous system-mediated effects of galanin-like peptide on lipid metabolism in liver and adipose tissue","volume":"6","author":"S Hirako","year":"2016","journal-title":"Scientific reports"},{"issue":"1","key":"pone.0249556.ref011","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/lt.22198","article-title":"Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events.","volume":"17","author":"I Laish","year":"2011","journal-title":"Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society."},{"issue":"1","key":"pone.0249556.ref012","doi-asserted-by":"crossref","first-page":"e0226873","DOI":"10.1371\/journal.pone.0226873","article-title":"Comparison of post-transplantation diabetes mellitus incidence and risk factors between kidney and liver transplantation patients","volume":"15","author":"VN Munshi","year":"2020","journal-title":"PloS one."},{"issue":"7","key":"pone.0249556.ref013","doi-asserted-by":"crossref","first-page":"517","DOI":"10.7326\/0003-4819-132-7-200004040-00002","article-title":"Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy","volume":"132","author":"Y Shiratori","year":"2000","journal-title":"Annals of internal medicine"},{"issue":"3","key":"pone.0249556.ref014","doi-asserted-by":"crossref","first-page":"174","DOI":"10.7326\/0003-4819-131-3-199908030-00003","article-title":"Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy","volume":"131","author":"H Yoshida","year":"1999","journal-title":"Annals of internal medicine"},{"issue":"3","key":"pone.0249556.ref015","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/jmv.24663","article-title":"Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection","volume":"89","author":"M Kobayashi","year":"2017","journal-title":"Journal of medical virology"},{"issue":"8","key":"pone.0249556.ref016","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00535-016-1304-z","article-title":"Hepatic vagus nerve regulates Kupffer cell activation via alpha7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis","volume":"52","author":"T Nishio","year":"2017","journal-title":"Journal of gastroenterology"},{"issue":"6","key":"pone.0249556.ref017","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.2353\/ajpath.2007.070112","article-title":"The myofibroblast: one function, multiple origins","volume":"170","author":"B Hinz","year":"2007","journal-title":"The American journal of pathology"},{"issue":"1","key":"pone.0249556.ref018","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/ar.a.20081","article-title":"Sympathetic nervous system regulation of liver repair","volume":"280","author":"JA Oben","year":"2004","journal-title":"The anatomical record Part A, Discoveries in molecular, cellular, and evolutionary biology."},{"key":"pone.0249556.ref019","article-title":"Innervation of the proximal human biliary tree","author":"A Zanchi","year":"2020","journal-title":"Virchows Archiv: an international journal of pathology"},{"issue":"4","key":"pone.0249556.ref020","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1155\/1993\/59691","article-title":"Hepatic branch vagotomy can suppress liver regeneration in partially hepatectomized rats.","volume":"6","author":"M Ohtake","year":"1993","journal-title":"HPB surgery: a world journal of hepatic, pancreatic and biliary surgery."},{"issue":"1","key":"pone.0249556.ref021","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1038\/s41467-018-07747-0","article-title":"Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation.","volume":"9","author":"T Izumi","year":"2018","journal-title":"Nature communications."},{"issue":"1","key":"pone.0249556.ref022","first-page":"328","volume":"67","author":"N Chalasani","year":"2018","journal-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases"},{"issue":"4","key":"pone.0249556.ref023","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s00535-015-1050-7","article-title":"Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"50","author":"S Watanabe","year":"2015","journal-title":"Journal of gastroenterology"},{"issue":"2","key":"pone.0249556.ref024","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/hep.510240201","article-title":"An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group","volume":"24","author":"P Bedossa","year":"1996","journal-title":"Hepatology (Baltimore, Md)."},{"issue":"9","key":"pone.0249556.ref025","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1111\/j.1572-0241.1999.01377.x","article-title":"Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions","volume":"94","author":"EM Brunt","year":"1999","journal-title":"The American journal of gastroenterology"},{"issue":"6","key":"pone.0249556.ref026","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":"RK Sterling","year":"2006","journal-title":"Hepatology (Baltimore, Md)."},{"issue":"1","key":"pone.0249556.ref027","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s00535-014-0946-y","article-title":"A novel serum marker, glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), for assessing liver fibrosis.","volume":"50","author":"T Toshima","year":"2015","journal-title":"Journal of gastroenterology"},{"issue":"10","key":"pone.0249556.ref028","doi-asserted-by":"crossref","first-page":"e0205541","DOI":"10.1371\/journal.pone.0205541","article-title":"Correction: Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels predict the presence of fibrotic nonalcoholic steatohepatitis (NASH) and NASH cirrhosis.","volume":"13","author":"N Alkhouri","year":"2018","journal-title":"PloS one."},{"issue":"10","key":"pone.0249556.ref029","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease","volume":"7","author":"AG Shah","year":"2009","journal-title":"Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association"},{"issue":"7","key":"pone.0249556.ref030","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":"M Abe","year":"2015","journal-title":"Journal of gastroenterology"},{"issue":"2","key":"pone.0249556.ref031","doi-asserted-by":"crossref","first-page":"165","DOI":"10.5009\/gnl.2007.1.2.165","article-title":"Decreased hepatic nerve fiber innervation in patients with liver cirrhosis","volume":"1","author":"SW Nam","year":"2007","journal-title":"Gut and liver"},{"issue":"5","key":"pone.0249556.ref032","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1034\/j.1600-0676.2001.210502.x","article-title":"Immunohistochemical and electron microscopic study of extrinsic hepatic reinnervation following orthotopic liver transplantation in rats","volume":"21","author":"T Takahashi","year":"2001","journal-title":"Liver"},{"issue":"1","key":"pone.0249556.ref033","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0041-1345(02)03809-5","article-title":"Regeneration of Schwann cells during extrinsic hepatic reinnervation following liver transplantation in rats","volume":"35","author":"I Sakamoto","year":"2003","journal-title":"Transplantation proceedings"},{"issue":"2","key":"pone.0249556.ref034","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/path.1711670210","article-title":"Hepatic reinnervation following orthotopic liver transplantation in man","volume":"167","author":"AP Boon","year":"1992","journal-title":"The Journal of pathology"},{"issue":"2","key":"pone.0249556.ref035","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/path.1711670209","article-title":"Immunohistochemical studies on the innervation of human transplanted liver","volume":"167","author":"AP Dhillon","year":"1992","journal-title":"The Journal of pathology"},{"issue":"4 Pt 1","key":"pone.0249556.ref036","first-page":"G439","article-title":"Role of the hepatic branch of the vagus nerve in liver regeneration in rats","volume":"253","author":"K Tanaka","year":"1987","journal-title":"The American journal of physiology"},{"issue":"2","key":"pone.0249556.ref037","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0002-9440(10)64208-3","article-title":"The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3","volume":"161","author":"D Cassiman","year":"2002","journal-title":"The American journal of pathology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249556","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T08:59:25Z","timestamp":1671872365000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249556"}},"subtitle":[],"editor":[{"given":"Tatsuo","family":"Kanda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,4,14]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0249556","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,14]]}}}