title: Inappropriate hepatic cholesterol synthesis expands the cellular pool of sterol available for recruitment by bile acids in the rat.
abstract: These studies test the hypothesis that a major determinant of excessive biliary cholesterol secretion is a level of hepatic sterol synthesis that is inappropriately high relative to the needs of the liver cell for preserving cholesterol balance. Biliary cholesterol secretion was measured in vivo in two models after loading the hepatocyte with sterol by two different mechanisms. In the first model, cholesterol was delivered physiologically to the liver in chylomicron remnants. This resulted in a sixfold increase in cholesteryl ester content and marked suppression of cholesterol synthesis, but biliary cholesterol secretion remained essentially constant. In the second model, 3-hydroxy-3-methyl-glutaryl CoA reductase levels in the liver were markedly increased by chronic mevinolin (lovastatin) administration. Withdrawal of the inhibitor resulted in a sudden fivefold increase in the rate of sterol synthesis in the liver of the experimental animals that was inappropriately high for cellular needs. This excessive synthesis, in turn, was accompanied by a fivefold increase in the cholesteryl ester content, enrichment of microsomal membranes with cholesterol and, most importantly, by a threefold increase in the rate of biliary sterol secretion. As the rate of sterol synthesis gradually returned to normal over 48 h, the cholesterol ester content, the lipid composition of the microsomal membranes, and rate of cholesterol secretion into bile also returned to baseline values. These results further support the concept of functional compartmentalization of cholesterol in the hepatocyte. Derangements that cause an inappropriately high rate of sterol synthesis in the endoplasmic reticulum may lead to an expansion of that pool of cholesterol that is recruitable by bile acids and, hence, to greater situation of the bile.
authors: Department of Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8887.
authors: L E
authors: LE
authors: Bilhartz
authors: D K
authors: DK
authors: Spady
authors: J M
authors: JM
authors: Dietschy
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001659:Biliary Tract / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005260:Female; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002788:Cholesterol Esters; D008563:Membrane Lipids; D013261:Sterols; D002784:Cholesterol; D008148:Lovastatin