Isolated livers were exposed to hypotonic perfusates. As shown previously, this hypotonic challenge leads to initial cell swelling, followed by volume regulatory ion fluxes, largely restoring cell volume within approximately 6 min. However, the hepatocyte is left in an altered metabolic state, which is characterized by marked stimulation of hepatic glutamine uptake and degradation and transient release of glutamate from the liver. Urea formation from glutamine and alanine is stimulated, whereas hepatic ammonia uptake and utilization for urea and glutamine synthesis decreases. These observations reveal a hitherto unrecognized factor modulating hepatic function during intestinal absorption.