Effect of adrenalectomy and hypophysectomy on the circadian rhythm of -hydroxy- -methylglutaryl coenzyme A reductase activity in rat liver.

The existence of a circadian rhythm of activity of the hepatic microsomal enzyme, /3-hydroxy-P-methylglutaryl coenzyme A reductase (/3-hydroxy-p-methylglutaryl-CoA reductase, EC 1.1.1.34), is well established. This rhythm was abolished after adrenalectomy; the resulting reductase activity was low and essentially constant at a level approximating that of intact rats killed at the nadir of their rhythm (i.e. noon). Adrenalectomized and intact rats consumed similar amounts of food daily and exhibited approximately the same cyclical pattern of eating. Hypophysectomy resulted in even lower reductase levels than adrenalectomy, and no circadian rhythm of reductase activity was found. Hypophysectomized rats consumed less food, and their cyclical pattern of eating was less evident than that of adrenalectomized or intact rats. The microsomes from normal and adrenalectomized rats gave no evidence of any significant changes in the kinetic properties (Km, pH optimum, and half-life of degradation) of /3-hydroxy-fl-methylglutaryl-CoA reductase. Replacement of adrenal hormones in adrenalectomized rats with single large doses of cortisone, cortisol, epinephrine, norepinephrine, or epinephrine plus cortisone resulted in little or no increase in reductase activity. However, intact rats, treated with epinephrine (0.05 mg/lOO g body weight) did show an increase of 2to 4-fold in reductase activity. This response appeared to require protein synthesis since it was blocked by cycloheximide. The available evidence suggests that intact functioning adrenal glands are necessary for the normal circadian rhythm of /3-hydroxy-fl-methylglutaryl-CoA reductase to occur, but does not indicate which hormone or hormones are involved, nor does it indicate whether such hormone (or hormones) play a direct or a permissive role.