Abstract 1187: Effects of Ezetimibe and/or Simvastatin on LDL Receptor Protein and on LDL Receptor and HMG-CoA Reductase Gene Expression in Mononuclear Blood Cells: A Randomized Trial in Healthy Men
Objective: Ezetimibe (cholesterol absorption inhibitor) and simvastatin are widely used in combination to treat hypercholesterolemia. The consequences of this combination therapy at a molecular level are unknown. Purpose of the present study was to examine the effects of ezetimibe, simvastatin and their combination on the LDL receptor (LDLR) and HMG-CoA reductase gene expression, on the LDLR protein expression and on the HMG CoA reductase activity in peripheral blood mononuclear cells (PBMCs).
Methods: Prospective, randomized, parallel 3-group trial. Three groups of 24 men each received a 14 day treatment with ezetimibe (10 mg/day), simvastatin (40 mg/day) or their combination, respectively. Blood drawing was performed on days 1 and 14. LDLR protein expression was measured by flow cytometry, LDLR and HMG-CoA gene expression using real-time RT-PCR, plasma lathosterol and desmosterol using GC/MS.
Results: LDL cholesterol decreased by 22±10%, 41±12%, and 60±10% in the ezetimibe, simvastatin and combination groups, respectively (P<0.0001 for all). Cholesterol synthesis (ratio of plasma lathosterol to cholesterol) was significantly decreased in the simvastatin group (P=0.03). The ezetimibe-treated group showed a compensatory increase in cholesterol synthesis, as reflected by the desmosterol to cholesterol ratio (P=0.02).The HMG-CoA reductase gene expression increased significantly by 33% and 36% in the simvastatin (P=0.015) and combination groups (P= 0.05) respectively, and remained unchanged in the ezetimibe group. Similarly, the LDLR gene expression increased significantly in the simvastatin (0.45±0.25 vs. 0.61±0.34, P=0.024) and combination groups (0.52±0.23 vs. 0.77±0.40, P=0.0012), but not in the ezetimibe group. The LDLR protein expression, however, remained unchanged in all groups.
Conclusions: Unlike simvastatin, the lipid-lowering effects of ezetimibe do not involve an upregulation of the HMG-CoA reductase or of the LDLR gene expression. Interestingly, the simvastatin-induced upregulation of the LDLR gene expression did not lead to an increase in the LDLR protein, suggesting the presence of posttranscriptional mechanisms that independently regulate LDLR protein abundance.