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Papers In Press, published online ahead of print January 16, 2005
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Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
Corresponding Author: john.dietschy{at}utsouthwestern.edu
The absorption of cholesterol by the small intestine is a major route for the net entry of cholesterol into the body and can therefore impact the plasma low density lipoprotein-cholesterol (LDL-C) concentration. These studies used ezetimibe, a potent inhibitor of cholesterol absorption, to delineate the biochemical and molecular changes in intrahepatic metabolism and biliary lipid secretion when there is a major reduction in chylomicron cholesterol delivery to the liver. In female LDL receptor (LDLR)-deficient mice fed a basal diet containing ezetimibe (0 to 10 mg/day/kg body weight), cholesterol absorption was reduced up to 91%, fecal neutral sterol excretion increased up to 4.7-fold and plasma total cholesterol concentrations fell by up to 18%. Blocking cholesterol absorption prevented accumulation of very low density lipoproteins and LDL in the circulation of LDLR-/- mice fed a lipid rich diet. In female LDLR+/+ mice fed the lipid-rich diet with ezetimibe, the relative mRNA level for the LDLR in the liver was 2-fold greater than in matching mice given the lipid-rich diet alone. We conclude that in the mouse the reduction in plasma LDL-C levels induced by blocking cholesterol absorption reflects both a diminished rate of LDL-C production as well as a modest increase in hepatic LDLR expression.
Revised on January 10, 2005
Accepted on January 12, 2005
Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption: Impact on low density lipoprotein production
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