Effects of perturbations in hepatic free and esterified cholesterol pools on bile acid synthesis,cholesterol 7α-hydroxylase,HMG-CoA reductase,acyl-CoA:Cholesterol acyltransferase and cytosolic cholesteryl ester hydrolase |
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Authors: | W M Grogan M L Bailey D M Heuman Z R Vlahcevic |
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Affiliation: | (1) Department of Biochemistry and Molecular Biophysics, McGuire Veterans Administration Hospital, Medical College of Virginia, Virginia Commonwealth University, 23298-0614 Richmond, Virginia;(2) Division of Gastroenterology, McGuire Veterans Administration Hospital, Medical College of Virginia, Virginia Commonwealth University, 23298-0614 Richmond, Virginia |
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Abstract: | Effects of expansion of the hepatic free cholesterol pool on bile acid and cholesterol metabolism and homeostasis were examined
in rats fed cholesterol in high-fat diets or treated with oleyl-p-(n-decyl)-benzenesulfonate (ODS) or progesterone. Cholesterol feeding for 10–16 days, which increased free (33%) and esterified
(6-fold) cholesterol, had no effect on cholate synthesis, total bile acid synthesis, or cholate turnover, whereas these activities
were increased 60–80% by ODS and progesterone, which produced only small increases (19%) in free cholesterol. Cholesterol
feeding reduced β-hydroxy-β-methylglutaryl (HMG)-CoA reductase (72%) and cholesteryl ester hydrolase (48%) and increased acyl-CoA:cholesterol
acyltransferase (184%), whereas ODS and progesterone reversed these compensatory responses in cholesterol-fed rats. Cholesterol
7α-hydroxylase was changed no more than 22% by any treatment. A bolus of ODS elevated biliary cholesterol output 41% and shifted
biliary bile acid synthesis and composition toward 12-deoxy bile acids. These effects were not seen in ODS-fed or progesterone-treated
rats, in which cholesteryl ester stores were depleted. It is concluded that effects of free cholesterol on bile acid synthesis
and biliary cholesterol are probably mediated by specific precursor or regulatory pools which can be independently regulated
and which represent a relatively small fraction of hepatic free cholesterol. |
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