title: Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: effects of LDL lowering by ezetimibe in the absence of statins.
abstract: OBJECTIVE
  To assess the lipid-lowering efficacy of ezetimibe in dyslipidemic cynomolgus monkeys comparing two dosing methods, and to evaluate PCSK9 plasma levels during dyslipidemia induction by feeding a high-fat/high-cholesterol diet (HFD), ezetimibe (Zetia(®), Ezetrol(®)) treatment, ezetimibe washout, and HFD washout.
  
  
  RESULTS
  Twenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100-400 mg/dL) were randomized into two groups and treated with ezetimibe for two weeks, either by oral gavage or by using food treats. The lipid-lowering effects of ezetimibe were identical between the two groups. After treatment, mean LDL cholesterol was decreased by 58% (174-72 mg/dL), total cholesterol by 42% (241-138 mg/dL), and PCSK9 levels were increased by 137% (147-314 ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol.
  
  
  CONCLUSIONS
  In a cynomolgus dyslipidemia model, PCSK9 levels are inversely correlated with LDL cholesterol in the absence of statin treatment, regardless whether lipid changes are modulated by diet or ezetimibe treatment.
authors.affiliation: Translational Medicine Research Centre (TMRC) Singapore, MSD, 8 Biomedical Grove, Neuros Buidling, Singapore 138665, Singapore. Electronic address: hannes.hentze@merck.com.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hentze
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Jensen
authors.forename: Ser Mien
authors.initials: SM
authors.lastname: Chia
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Shaw
authors.forename: Harry R
authors.initials: HR
authors.lastname: Davis
authors.forename: Shian-Jiun
authors.initials: SJ
authors.lastname: Shih
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D001384:Azetidines / Q000627:therapeutic use*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D008078:Cholesterol, LDL / Q000097:blood*; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000188:drug therapy*; D000069438:Ezetimibe; D008252:Macaca fascicularis; D043484:Proprotein Convertases / Q000097:blood*; D012697:Serine Endopeptidases / Q000097:blood*
chemical_list: D001384:Azetidines; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe
keywords: Dyslipidemia; Ezetimibe; Non-human primate; PCSK9