Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism. Evidence for a distinct biliary precursor pool.

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. IntroductionCholesterol gallstone disease is common in Western populations.

Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism.

“…However, as the contribution of cholesterol synthesis to biliary cholesterol secretion increased, the contribution from chylomicron remnants decreased. We postulated that these effects were due to suppression of ACAT activity by the progestin component of the contraceptive steroid mixture (64)(65)(66). With ACAT activity inhibited, any cholesterol entering the hepatocyte must leave as either biliary cholesterol, secreted VLDL, or newly synthesized bile acid.…”

Role of primary and secondary bile acids as feedback inhibitors of bile acid synthesis in the rat in vivo.

“…[ A micellar solution of 46.7 mM taurocholic acid, 0.3 mM cholesterol, and 4.9 mM dipalmitoyl lecithin (all from Sigma Chemical GmbH) was prepared as described by Stone et al (37). For a separate set of experiments pooled rat bile from normal animals with a bile fistula for up to 18 h was lyophilized and the residue dissolved in an infusate volume adequate for the required bile acid dose.…”

Short-term effects of simvastatin on bile acid synthesis and bile lipid secretion in human subjects

“…On direct examination of this relationship with the rat as an experimental model, most studies in which cholesterol synthesis was altered by different manipulations failed to reveal corresponding changes in biliary cholesterol output (9). Only when the rates of cholesterol synthesis could be subjected to sudden changes was it possible to disclose parallel alterations in cholesterol secretion into bile (10,11). Data in human subjects have shown that long-term administration of HMGCoA reductase inhibitors can induce a decrease of biliary cholesterol secretion and concentration (12)(13)(14).…”