Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Svenja Sydor, Paul Manka, Lea van Buren, Sarah Theurer, Suzan Schwertheim, Jan Best, Janette Heegsma, Ali Saeed, Diana Vetter, Martin Schlattjan, Anna Dittrich, Maria Isabel Fiel, Hideo A Baba, Alexander Dechêne, Francisco Javier Cubero, Guido Gerken, Ali Canbay, Han Moshage, Scott L Friedman, Klaas Nico FaberLars P Bechmann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (<80%) or high (>80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

Original languageEnglish
Pages (from-to)2172-2181
Number of pages10
JournalLiver International
Volume40
Issue number9
Early online date2020
DOIs
Publication statusPublished - 28-Jun-2020

Keywords

  • cholangiocellular carcinoma
  • cholestasis
  • FXR
  • KLF6
  • PROSTATE-CANCER PROGRESSION
  • DOWN-REGULATION
  • HEPATOCELLULAR-CARCINOMA
  • LIVER
  • ACTIVATION
  • DIAGNOSIS
  • ACID
  • HEPATOCARCINOGENESIS
  • PATHOGENESIS
  • MANAGEMENT

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