Failure of bile acids to control hepatic cholesterogenesis: evidence for endogenous cholesterol feedback

Abstract

Studies were undertaken to define the role of bile acids in the control of hepatic cholesterogenesis from acetate. Both biliary diversion and biliary obstruction increase the rate of sterol synthesis by the liver 2.5-to 3-fold. After biliary diversion, however, the bile acid content of the liver is decreased, whereas after biliary obstruction, it is markedly increased. Thus, there is no relationship between the tissue content of bile acid and the rate of hepatic cholesterol synthesis. Furthermore, restoration of the enterohepatic circulation of bile acid in animals with biliary diversion fails to prevent the rise in synthetic activity seen after this manipulation. These data indicate that bile acid plays no direct inhibitory role in the regulation of cholesterol synthesis by the liver.Other experiments were therefore undertaken to evaluate the possibility that changes in cholesterogenic activity observed after manipulation of the enterohepatic circulation of bile acid actually are the result of changes in the enterolymphatic circulation of cholesterol. In support of this thesis it was found that intestinal lymphatic diversion causes the same specific enhancement of cholesterol synthetic activity as biliary diversion and that both of these operative procedures increase enzymatic activity at the step mediated by P-hydroxy-P-methyl glutaryl reductase. Furthermore, the increase in the rate of sterol synthesis by the liver seen in animals with biliary diversion can be prevented by the infusion of approximately 7 mg of cholesterol/24 hr in the form of chylomicrons. This is an amount of cho-A portion of this work is presented in abstract form in 1968. Clin. Res. 16: 355. Dr. Dietschy is a Markle Scholar in Academic Medicine.

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

“…Again there was no significant difference in the food intake of bile acid fed rats and their controls (Fig.4). This lack of effect of bile acids is similar to that observed with bile fistula rats [4].…”

“…1 that cholic acid depresses hepatic HMG-CoA reductase activity in rats with lymphatic diversion. This conclusion seems to be contradictory to the one reported by Weiss and Dietschy [4]. From Fig.…”

“…The lowest amount of cholic acid given as a suspension in the experiments shown in Fig.1 is 37 pmoles/200 g body weight at each meal. This corresponds quite well with 35-40 pmoles of taurocholate infused per hour [4], if one assumes that it will take time for the cholic acid suspension to dissolve in the intestinal fluid. Under the conditions described here, this amount causes a strong depression of HMG-CoA reductase activity (Fig.…”

“…If the fistulated rats are fed with cholic acid, its action in liver can be studied independently from its effect in the resorption of cholesterol. While these experiments were in progress, Weiss and Dietschy [4] reported on the same problem. From their experiments these authors came to the conclusion that the bile acids affect cholesterol synthesis only by improving the intestinal resorption of cholesterol (see above alternative b).…”

“…I n addition the enhanced rate of hepatic cholesterol synthesis in animals with biliary obstruction [17] was used as evidence against an effect of bile acids in liver on cholesterogenesis [4]. However, the argument could as well be used against cholesterol as a regulator of cholesterol synthesis.…”