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.

Center of Cardiovascular Surgery and Transplantation Brno Brno Czech Republic

Centro de Investigacion Biomedica en Red Enfermedades Hepáticas y Digestivas Barcelona Spain

Department of Hepatology Imperial College London London UK

Department of Internal Medicine 3 University Hospital RWTH Aachen Pauwelsstraße 30 52074 Aachen Germany

Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN USA

Gastroenterology and Hepatology Unit University Hospital Marqués de Valdecilla Santander Spain

Hôpital Claude Huriez Services des Maladies de l'Appareil Digestif CHRU Lille and Unité INSERM 995 Lille France

Liver Unit Clinica Universidad de Navarra Hepatology Program Center for Applied Medical Research Pamplona Spain

Newcastle Fibrosis Research Group Biosciences Institute Faculty of Medical Sciences Newcastle University Newcastle UK

Pittsburgh Liver Research Center University of Pittsburgh Medical Center Pittsburgh PA USA

Research Institute Valdecilla Santander Spain

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Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis