Distribution and activity of glutamine synthase and carbamoylphosphate synthase upon enlargement of the liver lobule by repeated partial hepatectomies

Glutamine synthase and carbamoylphosphate synthase show a strikingly heterogeneous and fully complementary distribution in the rat liver. In the human liver, however, there is a midlobular zone where both enzymes are absent. The diameter of the human liver lobule is approximately twice the size of the rat lobule. To investigate whether lobule size is a major determinant for the expression patterns of glutamine synthase and carbamoylphosphate synthase, Wistar strain rats were partially hepatectomized 3 times, at weekly or monthly intervals. Due to hepatic regeneration the cross-sectional area of the liver lobules increased twofold. However, a midlobular zone which lacked expression of both glutamine synthase and carbamoylphosphate synthase did not develop in these livers, thus showing that lobular size is not a major determinant for the distribution patterns of glutamine and carbamoylphosphate synthase. The twofold increase in the cross-sectional area of the liver lobule was associated with a similar reduction in the relative number of glutamine synthase-positive cells and in the enzyme content of the liver, indicating that the regeneration process does not affect the pericentral pattern of glutamine synthase expression. After regeneration was complete, the glutamine synthase content in the liver was restored to its original value, demonstrating a twofold increase in the cellular concentration of glutamine synthase-positive hepatocytes. An increase in the diameter of the liver lobule was only seen after the first partial hepatectomy. Liver growth following subsequent partial hepatectomies can be explained by an increase in the length of the liver lobule and/or by splitting of liver lobules. The zonal distribution of DNA replication, which is characteristic of the first partial hepatectomy, is lost after repeated partial hepatectomies. Furthermore, evidence was obtained that the signal for inducing DNA synthesis may originate at the level of single liver units.