1. The rate limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, is found in the microsomal fraction of a liver homogenate. It is markedly inhibited in vitro by the cholesterol metabolites cholate, deoxycholate, chenodeoxycholate and their taurine conjugates only a t unphysiologically high concentrations.2. The inhibition by taurochenodoxycholate is non-competitive and only partially reversible. Therefore, the effect of bile salts in vitro is interpreted as a non-specific detergent effect.3. Feeding of cholic acid in the diet prevents the diurnal rhythm of the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The activity decreases with increasing time of feeding of cholic acid.4. The specific activity of the enzyme decreases with increasing age of the animals.5. It is concluded that the effect of bile salts in vitro on this enzyme cannot account for their effect in vivo. Rather, it is suggested that in vivo bile salts interfere with the de novo-synthesis and/or the degradation of the enzyme.

1.Cholic acid feeding strongly depresses the activity of the rate limiting enzyme of cholesterol synthesis in liver 3-hydroxy-3-methylglutaryl CoA reductase. Experiments were undertaken to decide between (a) a direct influence of the bile acid itself in liver or (b) an indirect effect of the bile acid by improving the intestinal resorption of cholesterol, which itself then would depress the activity of hepatic 3-hydroxy-3-methylglutaryl CoA reductase.2. For this purpose lymph fistula rats were fed with cholic acid. Compared with the control animals, which did not obtain cholic acid, the experimental groups showed strong depression of 3-hydroxy-3-methylglutaryl CoA reductase activity. This was only observed with animals killed during the dark period, i.e. when the rhythmically changing activity of the enzyme was high.3. A partial depression of the enzyme by fasting can be excluded, because animals fed with or without cholic acid, respectively, ingest the same amount of food.