Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase

We determined the extent to which diurnal varia- tion in cholesterol synthesis in liver is controlled by steady- state mRNA levels for the rate-limiting enzyme in the pathway, hydroxymethylglutaryl (HMG)-CoA reductase. Rats 30 days of age and maintained on a low-cholesterol diet since weaning were injected intraperitoneally with 3 H 2 O. The specific radio- activity of the whole-body water pool soon became constant, allowing for expression of values for incorporation of label into cholesterol as absolute rates of cholesterol synthesis. In liver, there was a peak of cholesterol synthesis from 8 PM to midnight, a 4-fold increase over synthesis rates from 8 AM to noon. Increases in synthesis were quantitatively in lock step with increases in mRNA levels for HMG-CoA reductase occur- ring 4 h earlier. In a parallel experiment, rats received 1% cholesterol in the diet from weaning to 30 days of age. Basal levels of hepatic cholesterol synthesis were greatly diminished and there was little diurnal variation of cholesterol synthesis or of levels of mRNA for HMG-CoA reductase. Levels of mRNA for the low density lipoprotein receptor and scavenger receptor-B1 (putative high density lipoprotein receptor) showed little diurnal variation, regardless of diet. This sug- gests that diurnal variation of hepatic cholesterol synthesis is driven primarily by varying the steady-state mRNA levels for HMG-CoA reductase. Other tissues were also examined. Ad- renal gland also showed a 4-fold diurnal increase in accumula- tion of recently synthesized cholesterol. In contrast to liver, however, there was little corresponding change in mRNA ex- pression for HMG-CoA reductase. Much of this newly synthe- sized cholesterol may be of hepatic origin, imported into ad- renal by SR-B1, whose mRNA was up-regulated 2-fold. In brain, there was no diurnal variation in either cholesterol syn- thesis or mRNA expression, and no influence of high- or low- cholesterol diets on synthesis rates or HMG-CoA reductase mRNA levels. —Jurevics, H., J. Hostettler, C. Barrett, P. Morell, and A. D. Toews. Diurnal and dietary-induced changes in cho- lesterol synthesis correlate with levels of mRNA for HMG- CoA reductase. J. Lipid Res. 2000. 41: 1048-1053.