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* Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
2 To whom correspondence should be addressed. e-mail: stephen.turley{at}utsouthwestern.edu
Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL-C) 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.
Abbreviations: ABCA1, adenosine triphosphate-binding cassette transporter A1; ABCB4, ABC transporter B4 (MDR2/3); ABCB11, ABC transporter B11 (SPGP/BSEP); ABCG5, ABC transporter G5; ABCG8, ABC transporter G8; ACAT-2, acyl CoA:cholesterol acyltransferase-2; DPS, digitonin-precipitable sterols; HMG-CoA red, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HMG-CoA syn, 3-hydroxy-3-methylglutaryl coenzyme A synthase
Supplementary key words liver • small intestine • bile acid • cholesterol efflux • cholesterol synthesis • fecal neutral sterol
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