Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption.
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.
Repa
Joyce J
JJ
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887, USA.
Turley
Stephen D
SD
Quan
Gang
G
Dietschy
John M
JM
D000042:Absorption; D000818:Animals; D001053:Apolipoproteins / Q000097:blood; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D017353:Gene Deletion; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001053:Apolipoproteins; D001647:Bile Acids and Salts; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol