Characteristics and Regulation of Hepatic Glutamine Transport

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Abstract
Glutamine is an important amino acid because of its key role in the transfer of both carbon and nitrogen between tissues in the body. Specific tissues are usually associated with either net synthesis or net utilization of glutamine, but the liver plays a central role in glutamine homeostasis, in that it can shift to function in either capacity. This capability, along with the localization of urea biosynthesis in the periportal hepatocytes, focuses attention on the transport mechanisms in hepatocytes for uptake and release of glutamine. Active transport of glutamine by hepatocytes is mediated by a Na+-dependent activity termed system N, which exhibits a rather narrow substrate specificity mediating uptake of histidine and asparagine as well as of glutamine. This secondary active transport system allows for the net accumulation of glutamine against a concentration gradient and maintenance of intracellular concentrations of glutamine between 4 and 8 mM in the face of a plasma concentration of 0.6 mM. Utilization of the Na+ electrochemical gradient as a driving force ensures that the system N carrier catalyzes a unidirectional transport event favoring the cytoplasm. It is obvious from the glutamine gradient across the plasma membrane that efflux of this amino acid is typically slower than accumulation; measurement of saturable, Na +independent glutamine transport by system L substantiates this proposal. However, it is clear that under certain metabolic conditions the liver represents a source of glutamine for other tissues in the body and net efflux must occur. The system N transport activity in hepatocytes is regulated by hormones such as insulin, glucagon, and glucocorticoids, as demonstrated both in vivo and in vitro. The carrier activity is also responsive to substrate availability, as evidenced by induction of transport activity in vivo in response to high-protein diets and in vitro by amino acid deprivation of cultured cells. In addition to these long-term regulatory controls that require de novo protein synthesis, presumably of the carrier itself, system N activity is subject to a rapid modulation by substrate amino acids of systems A and N. This response occurs within minutes of exposure to these amino acids and is protein synthesis independent. It is likely that this complex set of regulatory signals affects system N transport activity in vivo and serves to maintain intracellular levels of glutamine within the hepatocyte, as well as allowing the hepatocyte to monitor and maintain plasma levels in support of whole-body glutamine metabolism. The exact role of plasma membrane glutamine transport in whole-body glutamine homeostasis will require extensive experimentation at the cellular and molecular levels. (Journal of Parenteral and Enteral Nutrition14:51S-55S, 1990)