Regulation of rat liver β-hydroxy-β-methylglutaryl coenzyme A reductase activity and cholesterol levels of serum and liver in various dietary and hormonal states

The effects of hormones and dietary factors on rat liver β-hydroxy-β-methylglutaryl coenzyme A reductase activity and serum and liver cholesterol levels were tested. Cholestyramine feeding markedly stimulated reductase activity in the livers of rats depleted of insulin or l-triiodothyronine. Therefore, these hormones are not absolute requirements for the stimulation of reductase activity. In hypophysectomized rats, l-triiodothyronine markedly stimulated reductase activity, even when the animals were cholesterol fed or fasted. However, this stimulation was accompanied by a reduction of serum and liver cholesterol levels. In diabetic rats, insulin failed to either stimulate reductase activity after cholesterol feeding, or to depress the level of liver cholesterol. These results are consistent with a model in which cholesterol functions as a feedback repressor of reductase activity. In contrast, a number of dietary and hormonal states produced little or no change in the level of serum and liver cholesterol while producing widely different reductase activities. These results suggest that the cholesterol level does not regulate reductase activity and cholesterol synthesis and that the factors that affect the formation of cholesterol also have a similar effect on its degradation. However, the possibility of a small subcellular pool of cholesterol regulating reductase activity and thus showing a positive correlation cannot be ruled out. The results reported in this paper suggest that the repressor, in a feedback repression model of regulation, should have similar effects on the rate-limiting enzymes of cholesterol synthesis and degradation. In this way a factor that operates through the repressor affects the rates of synthesis and degradation, but not the level of liver and serum cholesterol.