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LIVER HYPOXIA LEADS TO THE UTILiSATION OF AMINO ACIDS BY THE CITRIC ACID CYCLE TO MAINTAIN ENERGY STORES
TS Chan1, S Gottschalk1, C Zwingmann1, P O’Brien2, D Mazer3, P Darby3, M Bilodeau1
1Centre de recherche, Centre hospitalier de l’Université de Montréal (CHUM), Hôpital St-Luc, Quebec; 2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario; 3Department of Anesthesia, Keenan Research Centre in the Li Ka Shing Knowledge Institute of St Michael’s Hospital, University of Toronto, Toronto, Ontario
Liver hypoxia occurs in a number of clinical conditions such as cirrhosis, portal vein thrombosis, low cardiac output and generalized hypoxemia. Liver hypoxia can contribute to liver atrophy and/or acute liver failure. Hypoxia has already been shown to decrease protein synthesis in isolated hepatocytes prior to ATP loss. Since aerobic metabolic pathways are linked to amino acid synthesis, we hypothesized that hypoxia could lead to decreased amino acid synthesis by the citric acid cycle and therefore contribute to decreased protein synthesis. Non-essential amino acids are synthesized from pyruvate, aspartate and glutamate (derived from the glycolytic and TCA cycle intermediates, pyruvate, oxaloacetate and alpha-ketoglutarate respectively). In a surgical model of liver ischemia (ligation of the left portal vein), we observed rapid hypoxia and metabolic changes in the ligated lobe. Aspartate and alanine levels decreased significantly during the first 3 hours following LPVL whereas glutamate levels (a recognized measure of the TCA cycle activity) increased. Interestingly, 6 hours after LPVL, we observed an increase in total succinate levels and a marked decrease in the percentage of succinate derived from glucose. Despite the presence of hypoxia, hepatic energy charge was maintained. These results could also be demonstrated in isolated rat hepatocytes incubated under anoxic conditions for 90 minutes. Furthermore, in isolated rat hepatocytes, the addition of aspartate and alpha-ketoglutarate (4 mM each) in combination afforded protection against anoxia-induced cell death and ATP loss. These results demonstrate that marked changes in amino acid metabolism occur during hypoxia. We suggest that this may be caused by increased anaplerotic activity (i.e. utilization of amino acids to replenish TCA cycle intermediates) for the purpose of maintaining ATP supply and hepatocyte viability.
This work was supported by a grant from the Canadian Institutes of Health Research and a fellowship grant from the CIHR in partnership with Fujisawa Inc. and the Canadian Association for the Study of the Liver (CASL)