title: SREBP-1c gene polymorphism is associated with increased inhibition of cholesterol-absorption in response to ezetimibe treatment.
abstract: 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 <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.
  
  
  RESULTS
  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).
  
  
  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-1 may be implicated in ezetimibe's mechanism of action.
authors: Medical Faculty of the University of Bonn, Clinical Pharmacology, Bonn, Germany.
authors: H K
authors: HK
authors: Berthold
authors: R
authors: R
authors: Laaksonen
authors: T
authors: T
authors: Lehtimäki
authors: H
authors: H
authors: Gylling
authors: W
authors: W
authors: Krone
authors: I
authors: I
authors: Gouni-Berthold
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe