Effect of dexamethasone on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and cholesterol synthesis in rat...

Dexamethasone increases reductase activity in cultured liver cells after a lag period of 2 h. The increases of activity are linear from 10(-9) to 10(-5) M dexamethasone, the maximum responses ranging from 2- to 4-fold. The increased reductase activity after dexamethasone treatment is not due to a change of the state of phosphorylation/dephosphorylation of the enzyme nor to an increase of cytosolic activating factor(s) for the reductase. Cholesterol synthesis, measured by incorporation of either [14C]acetate or 3H2O, increases 3-fold after dexamethasone (10(-6) M) treatment, as does the hydroxymethylglutaryl-CoA reductase activity, confirming that this enzyme is rate-controlling for cholesterol synthesis in cultured liver cells as it is in vivo. Dexamethasone (10 micrograms/100 g rat), given after onset of the light cycle, increases reductase activity over control rats at the nadir of the circadian cycle of this enzyme. When given after onset of the dark cycle, dexamethasone does not increase reductase activity over controls at the peak of their circadian cycle. Thus, physiologic doses of glucocorticoids partially reverse the decline in reductase activity due to the circadian rhythm.