Serum Transferrin As A Biomarker Of Hepatocyte Nuclear Factor 4 Alpha Activity And Hepatocyte Function In Liver Diseases

BMC Medicine
26 Feb, 2021 ,

Nurdan Guldiken et al. conducted a study to determine whether serum transferrin reflects the activity of hepatocyte nuclear factor 4 alpha (HNF4α) activity. The study involved 40 patients with advanced liver disease from whom serum and liver samples were collected. Diminished HNF4α and transferrin protein levels in individuals with cirrhosis were demonstrated via immunohistochemical and biochemical tests. From the results of the study, it could be concluded that serum transferrin levels could be a prognostic and mechanistic biomarker and could serve as a surrogate of impaired hepatic HNF4α signalling and liver failure.

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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 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 signalling and liver failure.