Hepatic glutamate metabolism: a tale of 2 hepatocytes

Glutamate plays a central role in hepatic amino acid metabolism, both because of its role in the transdeamination of most amino acids and because the catabolism of arginine, ornithine, proline, histidine, and glutamine gives rise to glutamate. It is now appreciated that different hepatic functions are restricted to hepatocyte subpopulations within different acinar zones. This is also a feature of glutamate metabolism. Glutamine catabolism and synthesis are physically separated by zonation, with glutamine synthetase restricted to a narrow band of hepatocytes in zone 3 of the hepatic acinus, whereas glutaminase occurs in zone 1. Arginine and ornithine metabolism is also restricted to particular hepatocyte subpopulations. Ornithine aminotransferase, the regulated enzyme of arginine and ornithine catabolism, is restricted to the same zone 3 cells as glutamine synthetase, whereas the urea cycle is found in the remaining hepatocytes. This separation facilitates the independent regulation of these 2 different metabolic processes. We know the acinar localization of only a small fraction of the approximately 15,000 genes expressed in the liver. Knowledge of the acinar localization of metabolic processes is essential for an appreciation of their relation to other hepatic functions and their regulation.