{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T22:08:55Z","timestamp":1775254135564,"version":"3.50.1"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019392","name":"NUTRIM","doi-asserted-by":"crossref","award":["Seeding Grant"],"award-info":[{"award-number":["Seeding Grant"]}],"id":[{"id":"10.13039\/501100019392","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-\u03b1, IL-6 and IFN-\u03b3) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0251822","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T17:32:05Z","timestamp":1621013525000},"page":"e0251822","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1895-4112","authenticated-orcid":true,"given":"Toon J. I.","family":"De Munck","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Boesch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Verhaegh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ad A. M.","family":"Masclee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisy","family":"Jonkers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos F.","family":"van Pelt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannie","family":"du Plessis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannelie","family":"Korf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik","family":"Nevens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ger H.","family":"Koek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Schalk","family":"Van der Merwe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jef","family":"Verbeek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"issue":"1","key":"pone.0251822.ref001","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":"ZM Younossi","year":"2016","journal-title":"Hepatology"},{"issue":"7","key":"pone.0251822.ref002","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1053\/j.gastro.2020.01.052","article-title":"Nonalcoholic Fatty Liver Disease 2020: The State of the Disease","volume":"158","author":"TG Cotter","year":"2020","journal-title":"Gastroenterology"},{"issue":"1","key":"pone.0251822.ref003","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"M Eslam","year":"2020","journal-title":"Journal of Hepatology"},{"issue":"7","key":"pone.0251822.ref004","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"M Eslam","year":"2020","journal-title":"Gastroenterology"},{"issue":"8","key":"pone.0251822.ref005","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"E Buzzetti","year":"2016","journal-title":"Metabolism"},{"issue":"15","key":"pone.0251822.ref006","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1056\/NEJMoa0808718","article-title":"Cold-Activated Brown Adipose Tissue in Healthy Men","volume":"360","author":"WD van Marken Lichtenbelt","year":"2009","journal-title":"New England Journal of Medicine"},{"issue":"3","key":"pone.0251822.ref007","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/j.1365-2036.2011.04723.x","article-title":"Association between the presence of brown adipose tissue and non-alcoholic fatty liver disease in adult humans","volume":"34","author":"Y Yilmaz","year":"2011","journal-title":"Alimentary Pharmacology & Therapeutics"},{"issue":"5","key":"pone.0251822.ref008","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.jhep.2016.01.025","article-title":"Metabolic interplay between white, beige, brown adipocytes and the liver","volume":"64","author":"L Scheja","year":"2016","journal-title":"J Hepatol"},{"issue":"1","key":"pone.0251822.ref009","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nrendo.2016.136","article-title":"Brown adipose tissue as a secretory organ","volume":"13","author":"F Villarroya","year":"2017","journal-title":"Nature Reviews Endocrinology"},{"issue":"12","key":"pone.0251822.ref010","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1038\/nm.3713","article-title":"The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis","volume":"20","author":"GX Wang","year":"2014","journal-title":"Nat Med"},{"issue":"12","key":"pone.0251822.ref011","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1172\/JCI96324","article-title":"Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression","volume":"127","author":"L Guo","year":"2017","journal-title":"J Clin Invest"},{"key":"pone.0251822.ref012","first-page":"26242","article-title":"Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4","volume":"6","author":"Y Ma","year":"2016","journal-title":"Gene Transfer. Sci Rep"},{"issue":"1","key":"pone.0251822.ref013","doi-asserted-by":"crossref","first-page":"e12289","DOI":"10.1111\/cob.12289","article-title":"Decreased serum neuregulin 4 levels associated with non-alcoholic fatty liver disease in children with obesity","volume":"9","author":"R Wang","year":"2019","journal-title":"Clin Obes"},{"issue":"12","key":"pone.0251822.ref014","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.metabol.2015.08.013","article-title":"A case-control study: Association between serum neuregulin 4 level and non-alcoholic fatty liver disease","volume":"64","author":"YN Dai","year":"2015","journal-title":"Metabolism"},{"issue":"3","key":"pone.0251822.ref015","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1053\/j.gastro.2015.05.044","article-title":"Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease","volume":"149","author":"J du Plessis","year":"2015","journal-title":"Gastroenterology"},{"issue":"7","key":"pone.0251822.ref016","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"DR Matthews","year":"1985","journal-title":"Diabetologia"},{"issue":"16","key":"pone.0251822.ref017","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the Metabolic Syndrome","volume":"120","author":"KGMM Alberti","year":"2009","journal-title":"Circulation"},{"issue":"Suppl 1","key":"pone.0251822.ref018","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.2337\/dc10-S062","article-title":"Diagnosis and classification of diabetes mellitus","volume":"33 Suppl 1","author":"A American Diabetes","year":"2010","journal-title":"Diabetes Care"},{"issue":"6","key":"pone.0251822.ref019","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"DE Kleiner","year":"2005","journal-title":"Hepatology"},{"issue":"1","key":"pone.0251822.ref020","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1148\/rg.291075123","article-title":"Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis","volume":"29","author":"FH Cassidy","year":"2009","journal-title":"Radiographics: a review publication of the Radiological Society of North America, Inc"},{"issue":"3","key":"pone.0251822.ref021","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/mrm.21561","article-title":"Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL","volume":"59","author":"H Kim","year":"2008","journal-title":"Magn Reson Med"},{"issue":"2","key":"pone.0251822.ref022","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/hep.23312","article-title":"Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease","volume":"51","author":"VW Wong","year":"2010","journal-title":"Hepatology (Baltimore, Md)"},{"key":"pone.0251822.ref023","doi-asserted-by":"crossref","DOI":"10.2202\/1544-6115.1027","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"GK Smyth","year":"2004","journal-title":"Stat Appl Genet Mol Biol"},{"issue":"9","key":"pone.0251822.ref024","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1093\/bioinformatics\/bti270","article-title":"Use of within-array replicate spots for assessing differential expression in microarray experiments","volume":"21","author":"GK Smyth","year":"2005","journal-title":"Bioinformatics"},{"issue":"1","key":"pone.0251822.ref025","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B (Methodological)"},{"issue":"12","key":"pone.0251822.ref026","doi-asserted-by":"crossref","first-page":"e0225705","DOI":"10.1371\/journal.pone.0225705","article-title":"Association between circulating neuregulin4 levels and diabetes mellitus: A meta-analysis of observational studies","volume":"14","author":"Y Wang","year":"2019","journal-title":"PLoS One"},{"issue":"4","key":"pone.0251822.ref027","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/cld.716","article-title":"Diagnostic challenges of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"11","author":"E Cleveland","year":"2018","journal-title":"Clin Liver Dis (Hoboken)"},{"issue":"6","key":"pone.0251822.ref028","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1097\/RLI.0b013e31824baff3","article-title":"Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard","volume":"47","author":"BK Kang","year":"2012","journal-title":"Invest Radiol"},{"issue":"3","key":"pone.0251822.ref029","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S2213-8587(13)70156-6","article-title":"Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study","volume":"2","author":"LEH Bakker","year":"2014","journal-title":"The Lancet Diabetes & Endocrinology"},{"issue":"1","key":"pone.0251822.ref030","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cmet.2014.12.008","article-title":"NRG4: an endocrine link between brown adipose tissue and liver","volume":"21","author":"A Pfeifer","year":"2015","journal-title":"Cell Metab"},{"issue":"17","key":"pone.0251822.ref031","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1038\/sj.onc.1202631","article-title":"Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase","volume":"18","author":"D Harari","year":"1999","journal-title":"Oncogene"},{"issue":"4","key":"pone.0251822.ref032","article-title":"Elevated circulating Neuregulin4 level in patients with diabetes","volume":"33","author":"LL Chen","year":"2017","journal-title":"Diabetes Metab Res Rev"},{"issue":"7","key":"pone.0251822.ref033","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1080\/09513590.2017.1420772","article-title":"Clinical significance of neuregulin 4 (NRG4) in gestational diabetes mellitus","volume":"34","author":"M Kurek Eken","year":"2018","journal-title":"Gynecol Endocrinol"},{"key":"pone.0251822.ref034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diabres.2016.04.007","article-title":"Comparison of serum Neuregulin 4 (Nrg4) levels in adults with newly diagnosed type 2 diabetes mellitus and controls without diabetes","volume":"117","author":"YE Kang","year":"2016","journal-title":"Diabetes Res Clin Pract"},{"issue":"2","key":"pone.0251822.ref035","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.diabet.2017.06.001","article-title":"The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus","volume":"44","author":"S Kralisch","year":"2018","journal-title":"Diabetes Metab"},{"issue":"1","key":"pone.0251822.ref036","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12916-016-0703-6","article-title":"Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study","volume":"14","author":"C Cai","year":"2016","journal-title":"BMC Med"},{"key":"pone.0251822.ref037","first-page":"6974191","article-title":"Plasma Neuregulin 4 Levels Are Associated with Metabolic Syndrome in Patients Newly Diagnosed with Type 2 Diabetes Mellitus","volume":"2018","author":"P Yan","year":"2018","journal-title":"Dis Markers"},{"issue":"1","key":"pone.0251822.ref038","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1161\/CIRCRESAHA.115.306647","article-title":"Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis","volume":"118","author":"G Hoeke","year":"2016","journal-title":"Circulation Research"},{"issue":"3","key":"pone.0251822.ref039","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.jhep.2009.05.023","article-title":"Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance","volume":"51","author":"NF Schwenzer","year":"2009","journal-title":"Journal of Hepatology"},{"issue":"6","key":"pone.0251822.ref040","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/MD.0b013e3182779d49","article-title":"Nonalcoholic fatty liver disease in lean individuals in the United States","volume":"91","author":"ZM Younossi","year":"2012","journal-title":"Medicine (Baltimore)"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251822","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T17:32:39Z","timestamp":1621013559000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251822"}},"subtitle":[],"editor":[{"given":"Robin D","family":"Clugston","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0251822","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,14]]}}}