TY - JOUR
T1 - Inappropriate hepatic cholesterol synthesis expands the cellular pool of sterol available for recruitment by bile acids in the rat
AU - Bilhartz, L. E.
AU - Spady, D. K.
AU - Dietschy, J. M.
PY - 1989
Y1 - 1989
N2 - 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 five-fold 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 saturation of the bile.
AB - 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 five-fold 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 saturation of the bile.
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U2 - 10.1172/JCI114283
DO - 10.1172/JCI114283
M3 - Article
C2 - 2794055
AN - SCOPUS:0024462420
SN - 0021-9738
VL - 84
SP - 1181
EP - 1187
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -