Effects of dietary cholesterol on bile formation and hepatic processing of chylomicron remnant cholesterol in the rat

Abstract

We have studied the coupling between hepatic uptake of chylomicron remnant cholesteryl ester and biliary excretion of cholesterol and bile acids in rats, after feeding them a cholesterol-free (control) or a high-cholesterol diet (1% wt/wt) for 2 wk. We equipped rats with permanent catheters in the bile duct, duodenum and heart to allow experiments in unanesthetized, unrestrained animals. Cholesterol feeding induced a 20% increase in plasma cholesterol concentration, a threefold increase in hepatic bile acid synthesis and a 27% increase in bile acid pool size, whereas biliary excretion of cholesterol was decreased by 50%. The enlarged bile acid pool contained relatively less cholic acid and more chenodeoxycholic acid and muricholic acids. [3H]cholesteryl ester-labeled chylomicron remnants (150 micrograms protein per rat) were injected intracardially, and blood and bile were collected for a period of 22 hr. Plasma disappearance of remnants was significantly delayed by cholesterol feeding, probably caused by competition with diet-induced beta-very low density lipoproteins for hepatic uptake. In control rats biliary excretion of chylomicron remnant-derived radioactivity (50% in free cholesterol and 50% in bile acids) showed an initial peak 1 hr after injection (2.4% dose per hour). A second peak (90% in bile acids), amounting to 1.5% of the dose per hour, appeared 11 hr after injection. Total 22-hr excretion of 3H was 22% of the dose. In cholesterol-fed rats chylomicron remnant-derived radioactivity appeared more rapidly in bile, with a peak 1 hr after injection, amounting to 3.5% of the dose per hour. In this case radioactivity was mainly present as bile acid. Total excretion in 22 hr was 27% of the dose. We conclude that chylomicron remnant uptake by the liver is efficiently coupled to bile acid synthesis and biliary excretion, thus providing an efficient pathway for removal of intestine-derived cholesterol. After cholesterol feeding, chylomicron remnant cholesteryl ester is more efficiently converted to bile acids, a mechanism which may contribute to the resistance of rats to diet-induced elevation of plasma cholesterol. In contrast, biliary excretion in the form of free cholesterol, the second main excretory pathway, is significantly decreased by a high-cholesterol diet.

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

“…This is probably because of the high basal level of bile acid synthesis on this diet, which was 3-fold increased compared with diet containing no cholesterol. 56 However, inhibition of hepatic ACAT may still contribute to the maintenance of this high basal level under conditions of a reduced transport of cholesterol to the liver by inhibition of intestinal ACAT. In addition, we found that there was no increase in the biliary excretion of cholesterol, indicating that ACAT inhibition does not result in a more lithogenic bile.…”

New insights into the mechanism of bile acid—induced biliary lipid secretion

“…'~' ,~~~ This finding is the more remarkable given the relatively minor contribution of plasma-derived to biliary lipid secretion. The application of liposomes to target-specific (phospho-)lipids to hepatocytes may phospho~ipids173.174 and cholestero167,1"7.1.58, 160,168,[175][176][177][178][179][180] be of valuable help to further dissect these proIn summary, the precise intracellular origins of the lipids, which are secreted into the bile, have not yet been identified indisputably. However, various novel experimental models offer promising opportunities t o approach these obscurities in the next few particularly when data were obtained to suggest that crystallization of cholesterol occurs from supersaturated vesicles.81~1ti3~210~214~217~21g~…”

“…The application of liposomes to target-specific (phospho-)lipids to hepatocytes may phospho~ipids173.174 and cholestero167,1"7.1. 58,160,168,[175][176][177][178][179][180] be of valuable help to further dissect these pro-In summary, the precise intracellular origins of the lipids, which are secreted into the bile, have not yet been identified indisputably. However, various novel experimental models offer promising opportunities t o approach these obscurities in the next few…”

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

“…Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans.…”

“…In particular, the pathway for metabolism of dietary cholesterol involves the hepatic uptake of chylomicron remnants and the use of chylomicron cholesterol for biliary secretion. [5][6][7][8] Therefore, it is crucial to compare the effect of APO-B48 -containing lipoproteins with that of APO-B100 -containing lipoproteins on regulating both the hepatic availability of dietary cholesterol for bile secretion and the risk for diet-induced cholesterol gallstones. In the present study, we investigated intestinal cholesterol absorption, gene expression levels of intestinal and hepatic lipid transporters, hepatic cholesterol and bile salt biosyntheses, biliary lipid secretion, and cholesterol gallstone formation in lithogenic diet-fed "APO-B48 only" and "APO-B100 only" mice compared with identically treated control wild-type mice.…”