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Journal of Lipid Research, Vol. 46, 779-789, April 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption
* Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887
Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887
1 To whom correspondence should be addressed. e-mail: 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 affect 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 (LDLR–/–) mice fed a basal diet containing ezetimibe (0–10 mg/day/kg body weight), cholesterol absorption was reduced up to 91%, fecal neutral sterol excretion was increased up to 4.7-fold, and plasma total cholesterol concentrations decreased by up to 18%. Blocking cholesterol absorption prevented the 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 and a modest increase in hepatic LDLR expression.
Abbreviations: ABCG1, adenosine triphosphate binding cassette transporter G1; apoA-I, apolipoprotein A-I; CYP, cytochrome P450; LDL-C, cholesterol carried in low density lipoprotein; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related protein; LXR, liver X receptor; NPC1L1, Niemann-Pick C1-like 1; SR-BI, scavenger receptor class B type 1
Supplementary key words cholesterol synthesis • cholesterol excretion • bile acid excretion • enterocyte • hepatocyte • biliary lipid composition • liver X receptor • adenosine triphosphate binding cassette transporters • apolipoprotein composition
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