Hepatocyte heterogeneity in glutamate uptake by isolated perfused rat liver

1 Glutamate is simultaneously taken up and released by perfused rat liver, as shown by 14 CO 2 production from [1‐ 14 C]glutamate in the presence of a net glutamate release by the liver, turning to a net glutamate uptake at portal glutamate concentrations above 0.3 mM. 2 14 CO 2 production from portal [1‐ 14 C]glutamate is decreased by about 60% in the presence of ammonium ions. This effect is not observed during inhibition of glutamine synthetase by methionine sulfoximine. 14 CO 2 production from [1‐ 14 C]glutamate is not influenced by glutamine. Also, when glutamate accumulates intracellularly during the metabolism of glutamine (added at high concentrations, 5 mM), 14 CO 2 production from [1‐ 14 C]glutamate is not affected. 3 If labeled glutamate is generated intracellularly from added [U‐ 14 C]proline, stimulation of glutamine synthesis by ammonium ions did not affect 14 CO 2 production from [U‐ 14 C]proline. 4 After induction of a perivenous liver cell necrosis by CCl 4 , i.e. conditions associated with an almost complete loss of perivenous glutamine synthesis but no effect on periportal urea synthesis, 14 CO 2 production from [1‐ 14 C]glutamate is decreased by about 70%. 5 The results are explained by hepatocyte heterogeneity in glutamate metabolism and indicate a predominant uptake of glutamate (that reaches the liver by the vena portae) by the small perivenous population of glutamine‐synthesizing hepatocytes, whereas glutamate production from glutamine or proline is predominantly periportal. In view of the size of the glutamine synthetase‐containing hepatocyte pool [Gebhardt, R. and Mecke, D. (1983) EMBO J. 2 , 567–570], glutamate transport capacity of these hepatocytes would be about 20‐fold higher as compared to other hepatocytes.