On the control of HMG-CoA reductase, a key regulatory enzyme of adrenal cholesterol synthesis

Abstract

In this study we have determined the effect of ACTH on the activity of HMG-CoA reductase in microsomes of hamster adrenals. Cycloheximide was used to study the dependence of the increased enzyme activity by ACTH on de novo protein synthesis. Microsomes were prepared and preincubated with and without NaF and in the presence or absence of phosphorylase phosphatase in order to differentiate between expressed (McNaF) and total (McPP) activity. ACTH induced (after 120 and 180 min) significant increases in HMG-CoA reductase activity with a latent period of 60 min for both McNaF and McPP preparations. Cycloheximide alone decreased the activity of the reductase and the coadministration of cycloheximide + ACTH caused a greater loss of activity. Also, both treatments produced an accumulation of free cholesterol in adrenals suggesting an increased turnover of the reductase by these substances. Preincubation of microsomes at 37°C enhanced per se HMG-CoA reductase activity, but the relative increase produced by ACTH treatments or endogenous ACTH remained essentially the same. In conclusion, under experimental conditions used, the enhancement of HMG-CoA reductase activity produced by ACTH seem to be due to increased enzyme synthesis.