{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:54:45Z","timestamp":1791482085673,"version":"4.3.4"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4\u03b1) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4\u03b1 activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic\/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In patients with advanced liver disease, serum transferrin levels correlated with hepatic\n                      <jats:italic>transferrin<\/jats:italic>\n                      expression (\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u20090.51,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01). Immunohistochemical and biochemical tests confirmed reduced HNF4\u03b1 and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4\u03b1 signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGF\u03b21), tumor necrosis factor \u03b1 (TNF\u03b1), interleukin 1 beta (IL-1\u03b2), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGF\u03b21 or the HNF4\u03b1 inhibitor BI6015 suppressed transferrin production, while exposure to TNF\u03b1, IL-1\u03b2, and IL-6 had no effect. The correlation between hepatic\n                      <jats:italic>HNF4A<\/jats:italic>\n                      and\n                      <jats:italic>transferrin<\/jats:italic>\n                      mRNA levels was also seen in advanced liver disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4\u03b1 signaling and liver failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-021-01917-6","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T02:53:56Z","timestamp":1613789636000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases"],"prefix":"10.1186","volume":"19","author":[{"given":"Nurdan","family":"Guldiken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josepmaria","family":"Argemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berivan","family":"Gurbuz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Oliverius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Fila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Hamesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Cabezas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Lozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Mathurin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay H.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Thursz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Bataller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Strnad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,17]]},"reference":[{"issue":"2","key":"1917_CR1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.jhep.2018.04.018","volume":"69","author":"D Kuscuoglu","year":"2018","unstructured":"Kuscuoglu D, Janciauskiene S, Hamesch K, Haybaeck J, Trautwein C, Strnad P. 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Patients with early alcoholic steatohepatitis (ASH) were obtained from Cliniques Universitaires Saint-Luc (Brussels, Belgium). All patients (or their legal representatives) gave written informed consent, and the research protocols were approved by the local Ethics Committees and by the central Institutional Review Board of the University of North Carolina at Chapel Hill [\n                      \n                      ].","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors declare that no support from any organization other than the below-mentioned ones for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3\u00a0years; and no other relationships or activities that could appear to have influenced the submitted work. Hence, all authors declare themselves to be independent from funders with respect to this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"39"}}