Vascular branching pattern and zonation of gene expression in the mammalian liver. A comparative study in rat, mouse, cynomolgus monkey, and pig.

BACKGROUND

A significant part of the liver volume consists of regions in which hepatocytes are in close contact with large branches of the afferent (portal vein) or efferent (hepatic vein) vessels. As most studies have addressed zonation of gene expression around the parenchymal branches of the portal and hepatic vein only, the patterns of gene expression in hepatocytes surrounding larger vessels are largely unknown.

METHODS

For that reason, we studied the patterns of expression of the mRNAs and proteins of the pericentral marker enzymes glutamine synthase, ornithine aminotransferase, and glutamate dehydrogenase and the periportal marker enzymes phosphoenolpyruvate carboxykinase and carbamoylphosphate synthase in the rat liver, in relation to the branching pattern of the afferent and efferent hepatic veins with immuno and hybridocytochemical techniques. These patterns of expression were compared with those seen in mouse, monkey, and pig liver.

RESULTS

The distribution patterns of the genes studied appear to reflect the "intensity" of the pericentral and periportal environment, glutamine synthase and phosphoenolypyruvate carboxykinase requiring the most pronounced environment, respectively. The patterns of gene expression around the large branches of the portal and hepatic vein were found to be related to the parenchymal branches in the neighbourhood of these large blood vessels. Only the cells of the limiting plate retain their periportal and pericentral phenotype for those marker enzymes that do not require a pronounced periportal or pericentral environment to be expressed. GS-negative areas in the pericentral limiting plate appear to correlate with a local absence of draining central veins, and become more frequent and extensive around the larger branches of the hepatic vein.

CONCLUSIONS

The similarity of the observed patterns of gene expression of the genes studied in mouse, rat, monkey, pig, and man suggests that they reflect a general feature of gene expression in the mammalian liver. A comparison of mouse, rat, pig, and human liver suggests that the presence of glutamine synthase-negative areas reflects the branching order of the efferent hepatic blood vessel.