Z Gastroenterol 2014; 52 - P_1_19
DOI: 10.1055/s-0033-1360863

Fxr-independent expression of the oncofetal marker Neighbor of Punc E11 after bile duct ligation in the adult mouse liver

A Bowe 1, V Hoffmann 1, CH Morten 2, S Schievenbusch 3, T Goeser 1, P Fickert 4, D Nierhoff 1
  • 1University of Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
  • 2University of Cologne, Institute for Genetics, Centre for Molecular Medicine, Cologne, Germany
  • 3Ludwig-Maximilians University Munich, Department of Internal Medicine IV, Division of Clinical Pharmacology and Center of Integrated Protein Science, Munich, Germany
  • 4Medical University of Graz, Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Dep of Internal Medicine, Graz, Austria
  • 5Medical University of Graz, Institute of Pathology, Graz, Austria

Background: Neighbor of Punc E11 (Nope) is strongly expressed in stem/progenitor cells of the fetal and adult liver as well as in hepatocellular carcinoma but is only weakly expressed in bile ducts of the adult liver. However, in mouse models with biliary liver injury (Mdr2-/-; DDC), Nope is additionally expressed in adult hepatocytes. Therefore we here further investigated the expression pattern of Nope after bile duct ligation in adult C57Bl/6 mice and in nuclear Farnesoid X Receptor (Fxr) -/- mice.

Methods: Liver tissue was extracted from adult C57Bl/6 mice and Fxr-/- mice after bile duct ligation. C57Bl76 mice were sacrificed after 24 hours to 5 weeks and FXR-/- mice 1 week postoperatively and liver tissue was tested for expression levels of Nope via quantitative RT-PCR. Costainings were performed for Nope in combination with biliary (CK19), epithelial-specific markers (E-cadherin), and stem cell markers (A6) as well as in combination with the canalicular membrane marker dipeptidylpeptidase (DPP) IV.

Results: Bile duct ligation leads to an increasing expression level of Nope in C57Bl/6 mice reaching a maximum level at week 3 postoperatively. While costainings with CK19 do not reveal Nope positive cholangiocytes, costainings with the canalicular marker DPPIV demonstrate the sinusoidal expression pattern of Nope on parenchymal hepatocytes. E-cadherin stains positive only on periportally located hepatocytes, while induction of Nope begins in zone 2 of the liver acinus, therefore showing only a minor overlap at early stages. At later stages after bile duct ligation, almost all of the parenchymal hepatocytes stain positive for Nope. There was no coexpression with A6 on Nope positive hepatocytes at any time. In Fxr-/- mice, induction of Nope shows a high expression level and similar pattern on parenchymal hepatocytes already at 1 week postoperatively.

Conclusion: We here report the induction of the novel oncofetal marker Nope in parenchymal hepatocytes after bile duct ligation. This induction is independent of the hepatocytic bile acid receptor Fxr and might indicate the dedifferentiation of hepatocytes due to cholestatic liver injury.