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@article{1759876,
author = {Guldiken, N and Argemi, J and Gurbuz, B and Atkinson, SR and Oliverius, M and Fila, Petr and Hamesch, K and Bruns, T and Cabezas, J and Lozano, JJ and Mann, J and Cao, S and Mathurin, P and Shah, VH and Trautwein, C and Thursz, MR and Bataller, R and Strnad, P},
article_location = {LONDON},
article_number = {1},
doi = {http://dx.doi.org/10.1186/s12916-021-01917-6},
keywords = {End-stage liver disease; Cirrhosis; Alcoholic hepatitis; Transferrin; HNF4alpha},
language = {eng},
issn = {1741-7015},
journal = {BMC MEDICINE},
title = {Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases},
volume = {19},
year = {2021}
}
TY - JOUR
ID - 1759876
AU - Guldiken, N - Argemi, J - Gurbuz, B - Atkinson, SR - Oliverius, M - Fila, Petr - Hamesch, K - Bruns, T - Cabezas, J - Lozano, JJ - Mann, J - Cao, S - Mathurin, P - Shah, VH - Trautwein, C - Thursz, MR - Bataller, R - Strnad, P
PY - 2021
TI - Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases
JF - BMC MEDICINE
VL - 19
IS - 1
PB - BIOMED CENTRAL LTD
SN - 17417015
KW - End-stage liver disease
KW - Cirrhosis
KW - Alcoholic hepatitis
KW - Transferrin
KW - HNF4alpha
N2 - 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.
ER -
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. Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases. \textit{BMC MEDICINE}. LONDON: BIOMED CENTRAL LTD, 2021, vol.~19, No~1, 12 pp. ISSN~1741-7015. Available from: https://dx.doi.org/10.1186/s12916-021-01917-6.
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