Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte

Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL33333391) concentrations. Ezetimibe (SCH 58235) and its analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol absorption whose mechanism of action is unknown. These studies...

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Main Authors: Joyce J. Repa, John M. Dietschy, Stephen D. Turley
Format: Article
Language:English
Published: Elsevier 2002-11-01
Series:Journal of Lipid Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227520327619
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spelling doaj-d617e06d6c274ea2b63e2a0b2bc6a71b2021-04-27T04:42:57ZengElsevierJournal of Lipid Research0022-22752002-11-01431118641874Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyteJoyce J. Repa0John M. Dietschy1Stephen D. Turley2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL33333391) concentrations. Ezetimibe (SCH 58235) and its analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol absorption whose mechanism of action is unknown. These studies investigated the effect of SCH 58053 on cholesterol metabolism in female 129/Sv mice. In mice fed a low cholesterol rodent diet containing SCH 58053, cholesterol absorption was reduced by 46% and fecal neutral sterol excretion was increased 67%, but biliary lipid composition and bile acid synthesis, pool size, and pool composition were unchanged. When the dietary cholesterol content was increased either 10- or 50-fold, those animals given SCH 58053 manifested lower hepatic and biliary cholesterol concentrations than did their untreated controls. Cholesterol feeding increased the relative mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1), ABC transporter G5 (ABCG5), and ABC transporter G8 (ABCG8) in the jejunum, and of ABCG5 and ABCG8 in the liver, but the magnitude of this increase was generally less if the mice were given SCH 58053.We conclude that the inhibition of cholesterol absorption effected by this new class of agents is not mediated via changes in either the size or composition of the intestinal bile acid pool, or the level of mRNA expression of proteins that facilitate cholesterol efflux from the enterocyte, but rather may involve disruption of the uptake of luminal sterol across the microvillus membrane.http://www.sciencedirect.com/science/article/pii/S0022227520327619liversmall intestinebile acidcholesterol effluxcholesterol synthesisfecal neutral sterol
collection DOAJ
language English
format Article
sources DOAJ
author Joyce J. Repa
John M. Dietschy
Stephen D. Turley
spellingShingle Joyce J. Repa
John M. Dietschy
Stephen D. Turley
Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
Journal of Lipid Research
liver
small intestine
bile acid
cholesterol efflux
cholesterol synthesis
fecal neutral sterol
author_facet Joyce J. Repa
John M. Dietschy
Stephen D. Turley
author_sort Joyce J. Repa
title Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
title_short Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
title_full Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
title_fullStr Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
title_full_unstemmed Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte
title_sort inhibition of cholesterol absorption by sch 58053 in the mouse is not mediated via changes in the expression of mrna for abca1, abcg5, or abcg8 in the enterocyte
publisher Elsevier
series Journal of Lipid Research
issn 0022-2275
publishDate 2002-11-01
description Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL33333391) concentrations. Ezetimibe (SCH 58235) and its analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol absorption whose mechanism of action is unknown. These studies investigated the effect of SCH 58053 on cholesterol metabolism in female 129/Sv mice. In mice fed a low cholesterol rodent diet containing SCH 58053, cholesterol absorption was reduced by 46% and fecal neutral sterol excretion was increased 67%, but biliary lipid composition and bile acid synthesis, pool size, and pool composition were unchanged. When the dietary cholesterol content was increased either 10- or 50-fold, those animals given SCH 58053 manifested lower hepatic and biliary cholesterol concentrations than did their untreated controls. Cholesterol feeding increased the relative mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1), ABC transporter G5 (ABCG5), and ABC transporter G8 (ABCG8) in the jejunum, and of ABCG5 and ABCG8 in the liver, but the magnitude of this increase was generally less if the mice were given SCH 58053.We conclude that the inhibition of cholesterol absorption effected by this new class of agents is not mediated via changes in either the size or composition of the intestinal bile acid pool, or the level of mRNA expression of proteins that facilitate cholesterol efflux from the enterocyte, but rather may involve disruption of the uptake of luminal sterol across the microvillus membrane.
topic liver
small intestine
bile acid
cholesterol efflux
cholesterol synthesis
fecal neutral sterol
url http://www.sciencedirect.com/science/article/pii/S0022227520327619
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