Berthold H K, Laaksonen R, Lehtimäki T, Gylling H, Krone W, Gouni-Berthold I
Medical Faculty of the University of Bonn, Clinical Pharmacology, Bonn, Germany.
Exp Clin Endocrinol Diabetes. 2008 May;116(5):262-7. doi: 10.1055/s-2007-993144. Epub 2007 Dec 10.
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).
Seventy-two healthy male subjects with LDL cholesterol <190 mg/dL participated in the study. Twenty four subjects were treated with ezetimibe (10 mg), simvastatin (40 mg) or their combination, respectively, for two weeks. Blood was drawn before and after the 2-week treatment period.
Eleven CC homozygous carriers of the gene were found (15%). There were no differences in cholesterol synthesis or 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).
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-1 may be implicated in ezetimibe's mechanism of action.
固醇调节元件结合蛋白1和2（SREBPs）是调节脂质代谢的转录因子。最近一项研究发现，SREBP - 1c基因多态性G952G的CC基因型与胆固醇合成增加有关。进一步的证据表明，SREBPs在胆固醇吸收中起作用，且SREBP基因多态性可调节对他汀类药物治疗的反应。本研究旨在探讨G952G多态性是否会改变胆固醇的合成和/或吸收，以及它是否会调节对广泛使用的降脂药物（如胆固醇合成抑制剂（辛伐他汀）或吸收抑制剂（依泽替米贝））的反应。
72名低密度脂蛋白胆固醇<190 mg/dL的健康男性受试者参与了该研究。24名受试者分别接受依泽替米贝（10 mg）、辛伐他汀（40 mg）或二者联合治疗，为期两周。在为期2周的治疗期前后采集血液样本。
发现11名该基因的CC纯合子携带者（15%）。通过血清羊毛甾醇、脱氢胆固醇和胆甾烯醇（合成标志物）与胆固醇的比率以及胆甾烷醇、谷甾醇和菜油甾醇（吸收标志物）来衡量，CC纯合子与G等位基因携带者在胆固醇合成或吸收方面没有差异。与G等位基因携带者相比，依泽替米贝在CC纯合子中阻断胆固醇吸收的效果显著更强（P = 0.002）。
在德国男性人群中，SREBP - 1基因的G/C（G952G）多态性与胆固醇合成或吸收无关。与G等位基因携带者相比，CC纯合子对依泽替米贝降低胆固醇吸收的作用反应显著增强，这表明SREBP - 1可能参与了依泽替米贝的作用机制。
