SREBP-1c gene polymorphism is associated with increased inhibition of cholesterol-absorption in response to ezetimibe treatment

Objective: Sterol regulatory binding proteins 1 and 2 (SREBPs) are transcription factors regulating lipid metabolism. A recent study has associated the CC genotype of the SREBP-1c polymorphism G952G with increased cholesterol synthesis. Further evidence suggests that SREBPs play a role in cholesterol absorption and that SREBP polymorphisms modulate the response to statin therapy. The present study examines whether the G952G polymorphism alters cholesterol synthesis and/or absorption and whether it modulates the response to widely used lipid-lowering drugs such as inhibitors of cholesterol synthesis (simvastatin) or absorption (ezetimibe). Methods: Seventy-two healthy male subjects with LDL cholesterol <190mg/dL participated in the study. Twenty four subjects were treated with ezetimibe (10mg), simvastatin (40mg) or their combination, respectively, for two weeks. Blood was drawn before and after the 2-week Results: Eleven CC homozygous carriers of the gene were found (15 %). There were no differences in cholesterol synthesis OF absorption between the CC homozygotes and the G allele-carriers, as measured by the ratios to cholesterol of serum lathosterol, desmosterol and cholestenol (synthesis markers) and cholestanol, sitosterol and campesterol (absorption markers). Ezetimibe had a significantly more potent effect in blocking cholesterol absorption in the CC homozygotes compared to the G-carriers (P=0.002). Conclusions: The G/C (G952G) polymorphism of the SREBP-1 gene is not associated with cholesterol synthesis or absorption in a German male population. The CC homozygotes have a significantly increased response to the effects of ezetimibe on cholesterol absorption compared to the G allele-carriers, suggesting that SREBP-I may be implicated in ezetimibe's mechanism of action. treatment period.