Glutamine transport and human hepatocellular transformation.
Among other functions, the liver serves to regulate both glucose and nitrogen economy in the body, and in humans, the amino acid glutamine is a major gluconeogenic substrate and the primary extrahepatic ammonia shuttle. Accordingly, the liver acinus possesses a unique heterogeneous metabolic architecture suited to carry out these functions with glutamine-consuming urea cycle and gluconeogenic enzymes in the periportal hepatocytes and a high capacity for glutamine synthesis in the perivenous hepatocytes, resulting in net glutamine balance across the hepatic bed under most conditions. Cytoplasmic levels of glutamine are significantly governed by the activity of the System N transporter in the plasma membrane of parenchymal cells; in this capacity, this glutamine carrier has been shown to represent a rate-limiting step in metabolism via glutaminase. The unique properties of System N allow it to rapidly adapt in support of the dynamic demands of whole body ammonia and glucose homeostasis. In contrast to System N in normal hepatocytes, human hepatoma cells take up glutamine at rates several-fold faster through a broad-specificity higher affinity transporter with characteristics of System ASC or B0. It is currently hypothesized that the expression of this high activity carrier by hepatoma cells combined with accelerated metabolism and tumor-induced derangements in hepatocellular architecture result in net glutamine consumption, and may underlie the diminished plasma glutamine levels observed in patients with hepatocellular carcinoma (HCC). The transport of glutamine through System ASC has been shown to regulate growth in some human hepatoma cells, which suggests this transporter may warrant consideration as a therapeutic target for HCC.
Bode
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BP
Massachusetts General Hospital Division of Surgical Oncology and Harvard Medical School, Boston 02114-2696, USA.
Souba
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WW
D001692:Biological Transport / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D005973:Glutamine / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008099:Liver / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism
D005973:Glutamine