Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism. Evidence for a distinct biliary precursor pool.
Open Access
- 1 November 1985
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 76 (5), 1773-1781
- https://doi.org/10.1172/jci112168
Abstract
Propensity for cholesterol gallstone formation is determined in part by biliary cholesterol content relative to bile salts and phospholipid. We examined the hypothesis that the rate of biliary cholesterol secretion can be controlled by availability of an hepatic metabolically active free cholesterol pool whose size is determined in part by rates of sterol synthesis, as reflected by activity of the primary rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and of sterol esterification, as reflected by the activity of the enzyme acyl coenzyme A/cholesterol acyltransferase (ACAT). Rats were prepared with biliary, venous, and duodenal catheters. The enterohepatic circulation of biliary lipids was maintained constant by infusion of a bile salt, lecithin, cholesterol replacement solution. Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h. By 2 h, ACAT activity and biliary cholesterol secretion were at control levels. Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16%. Administration of progesterone, an inhibitor of ACAT, had no effect on HMG CoA reductase and increased biliary cholesterol output 32% at 1 h. By 2 h, all parameters were near control levels. None of these agents had any significant effect on biliary bile salt or phospholipid secretion. Thus, acutely altering rates of esterification and/or synthesis can have profound effects on biliary cholesterol secretion independent of the other biliary lipids. These experiments suggest the existence of a metabolically active pool of free cholesterol that serves as a precursor pool for biliary cholesterol secretion. Furthermore, the size of this precursor pool is determined in part both by rates of cholesterol synthesis and esterification and is a key determinant of biliary cholesterol secretion.This publication has 47 references indexed in Scilit:
- Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.Journal of Lipid Research, 1979
- Active and inactive forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of the rat. Comparison with the rate of cholesterol synthesis in different physiological states.Journal of Biological Chemistry, 1979
- Effect of chenodeoxycholic acid and phenobarbital on the rate-limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones.1976
- Kinetic analysis of biliary lipid excretion in man and dog.JCI Insight, 1976
- Regulation of HMG-CoA ReductasePublished by Elsevier ,1976
- QUANTITATIVE-ANALYSIS OF CHOLESTEROL IN 5 TO 20 MU1 OF PLASMA1974
- Diurnal Variation in Biliary Lipid CompositionNew England Journal of Medicine, 1973
- A Method for Measurement of Cholesterol in Blood SerumClinical Chemistry, 1961
- Phosphorus Assay in Column ChromatographyJournal of Biological Chemistry, 1959
- A SIMPLIFIED METHOD FOR THE ESTIMATION OF TOTAL CHOLESTEROL IN SERUM AND DEMONSTRATION OF ITS SPECIFICITYJournal of Biological Chemistry, 1952