Moderately decreased cholesterol absorption rates are associated with a large atheroprotective effect.
OBJECTIVE
Human treatment with ezetimibe results in a moderate 50% to 54% decrease in cholesterol absorption and a 15% to 20% decrease in plasma LDL-cholesterol levels; nevertheless, the efficacy of ezetimibe therapy has been recently challenged by the ENHANCE trial. We examined the efficacy of a moderate decrease in cholesterol absorption in preventing atherosclerosis formation in the mouse.


RESULTS
Congenic 14DKK animals, consisting of a castaneus (CASA/Rk) chromosome 14 interval introgressed onto the C57BL/6J background, displayed a moderate decrease in cholesterol absorption rates. The effect of moderately decreased absorption on atherosclerosis formation was determined in 14DKK apolipoprotein E knockouts (14DKK-apoEKO). When compared to chow diet-fed control apoEKO mice, congenic 14DKK-apoEKO displayed a moderate 41% decrease in cholesterol absorption rates, 30% to 37% decrease in plasma cholesterol levels, and a 70% decrease in atherosclerosis formation. Studies on cholesterol efflux and reverse cholesterol transport (RCT) from 14DKK bone marrow-derived macrophages rejected a 14DKK interval-dependent atheroprotective effects that operate in macrophages. In contrast, 14DKK-apoEKO congenics were characterized by a 60% increase in RCT from peripheral tissue macrophages.


CONCLUSIONS
These studies strongly suggest that moderately decreased cholesterol absorption rates result in a large atheroprotective effect attributable to a decrease in plasma cholesterol levels and an increase in RCT from peripheral tissue macrophages.
Greenberg
Michael E
ME
Institute of Genomic Medicine, Cleveland Clinic, Ohio 44195, USA.
Smith
Jonathan D
JD
Sehayek
Ephraim
E
D000704:Analysis of Variance; D000818:Animals; D020296:Animals, Congenic; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D008078:Cholesterol, LDL / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011336:Probability; D011897:Random Allocation; D018709:Statistics, Nonparametric
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D008078:Cholesterol, LDL