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Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8
Liqing Yu1, Klaus von Bergmann, Dieter Lütjohann
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Journal of Lipid Research
|June 3, 2005
Summary
Blocking sterol absorption with ezetimibe lowers plant sterol levels and paradoxically increases cholesterol in mice lacking ABCG5 and ABCG8 transporters. This suggests ezetimibe can mitigate harmful plant sterol effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- ABCG5 (G5) and ABCG8 (G8) transporters regulate neutral sterol levels by limiting intestinal uptake and promoting biliary excretion.
- Mice lacking G5 and G8 (G5G8-/-) accumulate plant sterols but exhibit lower plasma and liver cholesterol despite impaired biliary cholesterol secretion.
Purpose of the Study:
- To investigate whether reduced biliary sterol secretion or dietary noncholesterol sterol accumulation drives altered hepatic sterol metabolism in G5G8-/- mice.
- To assess the impact of ezetimibe, a sterol absorption inhibitor, on sterol metabolism in G5G8-/- mice.
Main Methods:
- G5G8-/- mice were treated with ezetimibe for one month to inhibit sterol absorption.
- Sterol levels in plasma and liver were measured.
- mRNA levels of hepatic HMG-CoA reductase and synthase were quantified.
Main Results:
- Ezetimibe treatment significantly reduced sterol absorption and plasma levels of sitosterol and campesterol in G5G8-/- mice.
- Plasma and liver cholesterol levels increased in ezetimibe-treated G5G8-/- mice compared to controls.
- Increased hepatic cholesterol correlated with elevated mRNA levels of HMG-CoA reductase and synthase.
Conclusions:
- Pharmacological inhibition of sterol absorption can counteract detrimental effects of plant sterols, even without functional G5 and G8 transporters.
- Ezetimibe treatment demonstrates a potential therapeutic strategy for managing sterol-related metabolic disturbances.