Nurdan Guldiken1, Josepmaria Argemi2,3, Berivan Gurbuz1, Stephen R Atkinson4, Martin Oliverius5, Petr Fila5, Karim Hamesch1, Tony Bruns1, Joaquín Cabezas6,7, Juan J Lozano8, Jelena Mann9, Sheng Cao10, Philippe Mathurin11, Vijay H Shah10, Christian Trautwein1, Mark R Thursz4, Ramon Bataller2, Pavel Strnad12. 1. Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany. 2. Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 3. Liver Unit, Clinica Universidad de Navarra, Hepatology Program, Center for Applied Medical Research, Pamplona, Spain. 4. Department of Hepatology, Imperial College London, London, UK. 5. Center of Cardiovascular Surgery and Transplantation Brno, Brno, Czech Republic. 6. Research Institute Valdecilla (Instituto de Investigación Sanitaria Valdecilla), Santander, Spain. 7. Gastroenterology and Hepatology Unit, University Hospital Marqués de Valdecilla, Santander, Spain. 8. Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 9. Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK. 10. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. 11. Hôpital Claude Huriez, Services des Maladies de l'Appareil Digestif, CHRU Lille, and Unité INSERM 995, Lille, France. 12. Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany. pstrnad@ukaachen.de.
Abstract
BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: 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. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), 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 TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: 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. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), 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 TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
Authors: Matthew E Ritchie; Belinda Phipson; Di Wu; Yifang Hu; Charity W Law; Wei Shi; Gordon K Smyth Journal: Nucleic Acids Res Date: 2015-01-20 Impact factor: 16.971
Authors: Fin Stolze Larsen; Lars Ebbe Schmidt; Christine Bernsmeier; Allan Rasmussen; Helena Isoniemi; Vishal C Patel; Evangelos Triantafyllou; William Bernal; Georg Auzinger; Debbie Shawcross; Martin Eefsen; Peter Nissen Bjerring; Jens Otto Clemmesen; Krister Hockerstedt; Hans-Jørgen Frederiksen; Bent Adel Hansen; Charalambos G Antoniades; Julia Wendon Journal: J Hepatol Date: 2015-08-29 Impact factor: 25.083