Coordinate Induction of the Urea Cycle Enzymes by Glucagon and Dexamethasone Is Accomplished by Three Different Mechanisms

Abstract

Induction of the mRNAs of the five urea cycle enzymes by glucagon and dexamethasone was studied in cultured rat hepatocytes to define mechanisms which coordinate the increases in the enzyme activities by these hormones. The transcription rate for arginase mRNA increased 9-fold in 7 h, the mRNA level 90-fold in 28 h, and the arginase activity 1.5-fold at 48 h, suggesting that induction is due primarily to stabilization of mRNA. Arginase mRNA induction was minimal with either hormone alone, combined hormones were synergistic, and cycloheximide pretreatment did not prevent the rise in mRNA levels. Carbamyl phosphate synthetase mRNA levels responded synergistically to the combined hormones and peaked 240-fold above controls at 24 h although activity only increased 1.4-fold at 48 h. Argininosuccinate lyase and synthetase mRNAs were induced by an increased transcriptional rate, were not induced by single hormones, responded synergistically to combined hormones, and showed a partial blockage of mRNA induction by cycloheximide. The ornithine transcarbamylase mRNA level was not increased by these hormones although activity increased 1.3-fold, suggesting stabilization of the enzyme. Thus glucagon and dexamethasone induce the urea cycle enzymes by three different mechanisms: transcriptional control of mRNA in argininosuccinate synthetase and lyase, stabilization of mRNA in carbamyl phosphate synthetase and arginase, and protein stabilization of ornithine transcarbamylase.