In hepatocytes from fasted rats, several amino acids are known to stimulate glycogen synthesis via activation of glycogen synthase. The hypothesis that an increase in cell volume resulting from amino acid uptake may be involved in the stimulation of glycogen synthesis is supported by the following observations. 1) The extent of stimulation of glycogen synthesis by both metabolizable and nonmetabolizable amino acids was directly proportional to their ability to increase cell volume, except for proline, which stimulated glycogen synthesis more than could be accounted for by the increase in cell volume. 2) Both cell swelling and stimulation of glycogen synthesis by amino acids were prevented when hepatocytes were incubated in hyperosmotic media containing sucrose or raffinose. 3) Increasing the cell volume by incubating hepatocytes in Na+-depleted media in the absence of amino acids also stimulated glycogen synthesis. 4) Stimulation of glycogen synthesis by Na+ depletion was prevented by restoring the normal osmolarity with sucrose, but not with choline chloride which, by itself, stimulated glycogen synthesis and increased cell volume.
It is concluded that stimulation of glycogen synthesis by amino acids is due, at least in part, to an increase in hepatocyte volume resulting from amino acid uptake, and that hepatocyte swelling per se stimulates glycogen synthesis.