Influence of Bile Acids on the Activity of Rat Liver 3‐Hydroxy‐3‐methylglutaryl Coenzyme A Reductase

Abstract

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.

Influence of Bile Acids on the Activity of Rat Liver 3‐Hydroxy‐3‐methylglutaryl Coenzyme A Reductase

“…This result is in agreement with the effect observed with rats that were fed a cholic acid supplemented diet [2]. Lymph fistula rats not fed with the bile acid (3 different experiments) show a slight increase of HMG-CoA reductase activity when compared with the corresponding group of sham operated animals (Fig.1).…”

“…Consistent with this phenomenon is the observation that under the same conditions the specific activity of HMO-CoA reductase sinks to very low values [2]. HMG-CoA reductase catalyzes the rate limiting step of cholesterol synthesis, the reduction of HMG-CoA to mevalonate.…”

“…It is not clear, why, after infusion of bile acids into bile fistula rats, no decrease of cholesterogenesis is found a t 9:OO h [4]. However, since bile acids partially prevent the rhythmic increase of HMG-CoA reductase activity at night [2], one should investigate the kinetics of formation and degradation of this enzyme in order to find the answer to this discrepancy.…”

Inhibition of Cholesterol Synthesis in Rat Liver by Physiological Doses of Taurocholate

“…First, experiments performed in vitro [7,8] and in thc perfused liver [24,25] gave no evidence of a rapid inhibition of cholesterogenic enzymes by bile salts. Moreover, wc observed a coincidence of a greater sensitivity of inhibition by bile salts apparent at 22 h with the diurnal phase of most active synthesis of the 3-hydroxy-3-methylglutarylCoA reductase protein [26].…”

The influence of bilateral superior cervical ganglionectomy, continuous light and continuous darkness on the diurnal rhythm of hydroxymethylglutaryl‐coenzyme a reductase in rat liver

“…Similarly, the food intake changes periodically, i.e. rats eat much more during the dark period than during the light period [6]. If rats have access to food only for a brief fraction of the light period, the maximum of activity of HMGCoA reductase is found in the light period [4].…”