Fine Structure of the Cyclic Rhythm of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase. Differential Effects of Cholesterol Feeding and Fasting

Rat liver microsomal 3-hydroxy-3-methylglutaric acid (HMG)-CoA reductase (mevalonate:NADP-oxidore-ductase (acylating CoA), EC 1.1.1.34) undergoes striking cyclic variations which are dependent on protein synthesis. Distinct activity peaks are observed at about midnight and 1:45 a.m. (EST). Cycloheximide prevents both the initial (6 p.m. to midnight) rise in HMG-CoA reductase activity and the second rise which occurs between 12:30 a.m. and 1:45 a.m. A rapid, 35-45% decrease in HMG-CoA reductase activity is observed from midnight to about 12:30 a.m. After the second cyclic peak at about 1:45 a.m., reductase activity declines, reaching basal levels in midmorning. In rats fasted for 36 hr reductase activity decreases 20 to 25-fold. Nevertheless, the cyclic rhythm with both peaks in activity persists in rats fasted for 36 hr. This suggests that cyclic variations in amino acid and tryptophan intake are not responsible for the cyclic rhythm in HMG-CoA reduction. Short duration (1018 hr) cholesterol feeding resulted in an overall decline in reductase activity from 6 p.m. to midnight. Activity in rats fasted 10^-18 hr increases severalfold during this time. The different effects of cholesterol feeding and fasting suggest that they may regulate HMG-CoA reductase through different mechanisms.