Loss of zonation in end stage liver disease revealed by in situ omics

F Reichel; M Brosch; K Kattler; A Herrmann; W von Schönfels; K Nordström; D Seehofer; G Damm; T Becker; S Zeissig; S Nehring; V Moser; RV Thangapandi; F Stickel; G Baretton; C Röcken; M Muders; M Matz-Soja; M Krawczak; G Gasparoni; H Hartmann; A Dahl; C Schafmayer; J Walter; J Hampe

doi:10.1055/s-0038-1677180

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2019; 57(01): e50-e51
DOI: 10.1055/s-0038-1677180

3. Metabolism (incl. NAFLD)

Georg Thieme Verlag KG Stuttgart · New York

Loss of zonation in end stage liver disease revealed by in situ omics

Authors

F Reichel

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany
M Brosch

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany
K Kattler

²Department of Genetics & Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
A Herrmann

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany
W von Schönfels

³Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
K Nordström

²Department of Genetics & Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
D Seehofer

⁴Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig, Germany
G Damm

⁴Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig, Germany
T Becker

³Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
S Zeissig

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
S Nehring

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
V Moser

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
RV Thangapandi

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany
F Stickel

⁵Department of Gastroenterology, University of Zürich, Zürich, Switzerland
G Baretton

⁶Institute of Pathology, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
C Röcken

⁷Institute of Pathology, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
M Muders

⁶Institute of Pathology, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
M Matz-Soja

⁸Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, Leipzig/Germany
M Krawczak

¹⁰Institute of Medical Informatics and Statistics, Christian-Albrechts University, Kiel, Germany
G Gasparoni

²Department of Genetics & Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
H Hartmann

¹¹Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden (TU Dresden), Dresden Germany
A Dahl

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany
C Schafmayer

³Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
J Walter

²Department of Genetics & Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
J Hampe

¹Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany

⁹Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden Germany

Abstract

Full Text

Zonation of liver metabolism and its regulation has been intensely studied in the past but was focused on the healthy organ and animal models. Major break throughs were accomplished especially using so called omics-techniques. Although liver cirrhosis has become one of the major problems in the western world, it was not yet achieved to use those methods at this stage of disease progression.

Here we present the first study on transcriptomes of hepatocytes spatially extracted from human cirrhotic liver samples, innovatively combining the two powerful methods of laser capture microdissection and deep whole genome RNA-sequencing.

We were able to detect that the functional zonation of the liver lobule and its gradients of enzyme and other protein coding mRNA between the periportal fields and the central vein is completely compromised in the stage of liver cirrhosis. This refers to plenty of key enzymes of the major pathways of the metabolism of the liver including the expression of glutamine synthetase. This can primarily be explained by the loss of formerly zonation-inducing pathways. The sacrificed zonated Wnt-signaling activity may be a major cause for the loss of a characteristically pericentral gene expression thus leading to the process of portalisation of hepatocytes throughout the liver.

Overall our data provides a deeper understanding for the deregulation of liver zonation and its consequences for liver functions in end stage liver disease eventually leading to the failure of the organ.