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

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.