Glutamine and cell signaling in liver

Abstract

In the liver, glutamine plays an important role in ammonia detoxication and the regulation of pH homeostasis ("intercellular glutamine cycle"). In addition, this amino acid regulates liver metabolism and transport by mechanisms that cannot be attributed to its metabolism. Examples include the stimulation of protein and glycogen synthesis and bile acid secretion and the inhibition of proteolysis in liver. The major trigger for such effects is an increased hepatocyte hydration due to the cumulative uptake of glutamine into the cells, which activates osmosignaling pathways involving mitogen-activated protein kinases (MAPK). Glutamine- and hypoosmolarity-induced cell swelling activates extracellular signal-regulated kinases (ERK) and p38(MAPK). Activation of these MAPK results in an increased capacity of bile acid excretion into bile due to a rapid translocation of canalicular transport ATPases from a subcanalicular storage compartment to the canalicular membrane. Similarly, glutamine augments biliary excretion of cysteinyl leukotrienes in endotoxin-treated rat livers. Also, the antiproteolytic effect of glutamine is largely due to glutamine-induced cell swelling, which activates osmosignaling pathways. Here, the glutamine-induced p38(MAPK) activation mediates the inhibition of autophagic proteolysis at the level of autophagosome formation.