J 2021

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases

GULDIKEN, N, J ARGEMI, B GURBUZ, SR ATKINSON, M OLIVERIUS et. al.

Basic information

Original name

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases

Authors

GULDIKEN, N, J ARGEMI, B GURBUZ, SR ATKINSON, M OLIVERIUS, Petr FILA, K HAMESCH, T BRUNS, J CABEZAS, JJ LOZANO, J MANN, S CAO, P MATHURIN, VH SHAH, C TRAUTWEIN, MR THURSZ, R BATALLER and P STRNAD

Edition

BMC MEDICINE, LONDON, BIOMED CENTRAL LTD, 2021, 1741-7015

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 11.150

DOI

UT WoS

000618748900001

Keywords in English

End-stage liver disease; Cirrhosis; Alcoholic hepatitis; Transferrin; HNF4alpha
Změněno: 14/4/2021 20:33, MUDr. Petr Fila, Ph.D.

Abstract

V originále

Background Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4 alpha 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 HNF4 alpha and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4 alpha signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGF beta 1), tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), 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 beta 1 or the HNF4 alpha inhibitor BI6015 suppressed transferrin production, while exposure to TNF alpha, IL-1 beta, 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 HNF4 alpha signaling and liver failure.