Mechanism of activation of liver acetyl‐CoA carboxylase by cell swelling

Abstract

The activation of hepatic glycogen synthase by the amino‐acid‐induced cell swelling has been attributed to the stimulation of [glycogen‐synthase]‐phosphatase resulting from an increase in the intracellular content in glutamate and aspartate, and a decrease in intracellular Cl−, which is a compensatory response to cell swelling [Meijer, A. J., Baquet, A., Gustafson, L., van Woerkom, G. M. & Hue, L. (1992) J. Biol. Chem. 267, 5823–5828]. Here we studied whether the activation of acetyl‐CoA carboxylase by cell swelling could be explained by the same mechanism. The activation of endogenous or purified acetyl‐CoA carboxylase was measured in gel‐filtered liver extracts or cytosols. No activation could be observed under basal conditions but a fivefold stimulation was obtained with concentrations of glutamate (20–25 mM) found in hepatocytes incubated with glutamine. A similar stimulation was also observed with other dicarboxylic acids such as malonate and succinate, or with metal ions like Mg2+, Ca2+ and Mn2+ (10 mM). The addition of 50–100 mM Cl− was found to inhibit the activation of acetyl‐CoA carboxylase by some 20–30%. Mg2+ was also found to stimulate the activation of the endogenous glycogen synthase. The glutamate‐stimulated and Mg2+‐stimulated activation of glycogen synthase and acetyl‐CoA carboxylase was unaffected by 10 μM inhibitor‐2, a specific inhibitory protein of protein phosphatase‐1, but could be nearly completely blocked by the phosphatase inhibitor microcystin‐LR. Our data suggest that the amino‐acid‐induced activation of acetyl‐CoA carboxylase and glycogen synthase in the liver occurs by a common ionic mechanism. Copyright © 1993, Wiley Blackwell. All rights reserved