Abstract
BackgroundSerum 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.MethodsFactors 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.ResultsIn 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.ConclusionsSerum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
Highlights
Serum transferrin levels represent an independent predictor of mortality in patients with liver failure
Patients with advanced liver disease display decreased hepatic transferrin expression To delineate the factors underlying the predictive usefulness of transferrin in severe liver disease, we compared the hepatic expression of transferrin and transferrin serum levels in 23 patients with advanced liver disease and available matched mRNA-serum sample pairs (Table 1)
Serum transferrin levels did not correlate with serum levels of other established hepatocellular products such as alpha1-antitrypsin, ceruloplasmin, albumin, or apolipoprotein B
Summary
Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. The levels of these proteins are diminished in advanced liver disease as they reflect the loss in hepatocytes [1]. Apart from that, the protein synthesis within hepatocytes is subject to a complex regulation by liver-enriched transcription factors (LETFs). Hepatocyte nuclear factors constitute prototypical LETFs and regulate the production of multiple liver-specific proteins [2, 3]. Various cytokines such as interleukins 1 and 6 or tumor necrosis factor α (TNFα) induce the synthesis of species known as acute-phase proteins (APPs) and diminish the production of negative APPs [1, 4]. Serum levels of negative APPs constitute attractive biomarkers reflecting both the hepatocellular mass and the amount of superimposed systemic stress or inflammation [1, 6]. Transferrin emerges as a mortality predictor in sepsis and multiple liver disorders [1, 6, 7]
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