title: Leoligin, the major lignan from Edelweiss, activates cholesteryl ester transfer protein.
abstract: OBJECTIVE
  Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity.
  
  
  METHODS
  A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n=20) and rabbit plasma (n=3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n=5 for each treatment group).
  
  
  RESULTS
  In vitro, leoligin significantly activated CETP in human plasma at 100 pM (p=0.023) and 1 nM (p=0.042), respectively, whereas leoligin concentrations of 1 mM inhibited CETP activity (p=0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p=0.015). There was no short-term toxicity apparent in mice treated with leoligin.
  
  
  CONCLUSIONS
  CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism.
authors.affiliation: Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Kristina
authors.initials: K
authors.lastname: Duwensee
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwaiger
authors.forename: Ivan
authors.initials: I
authors.lastname: Tancevski
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.forename: Miranda
authors.initials: M
authors.lastname: van Eck
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Tobias
authors.initials: T
authors.lastname: Linder
authors.forename: Ursula
authors.initials: U
authors.lastname: Stanzl
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritsch
authors.forename: Josef R
authors.initials: JR
authors.lastname: Patsch
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
authors.forename: Philipp
authors.initials: P
authors.lastname: Eller
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000819:agonists*; D006801:Humans; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D011817:Rabbits
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D017705:Lignans; C542788:leoligin