title: Leoligin, the major lignan from Edelweiss, inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase and reduces cholesterol levels in ApoE-/- mice.
abstract: The health benefit through the control of lipid levels in hyperlipidaemic individuals is evident from a large number of studies. The pharmacological options to achieve this goal shall be as specific and personalized as the reasons for and co-factors of hyperlipidaemia. It was the goal of this study to reveal the impact of leoligin on cholesterol levels and to define its mechanism of action. Oral application of leoligin in ApoE-/- mice led to significantly reduced total serum cholesterol levels and a reduction in postprandial blood glucose peak levels. In the absence of biochemical signs of toxicity, leoligin treatment resulted in reduced weight gain in mice. The effects of leoligin on serum cholesterol levels may be due to a direct inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) by a unique, non-statin-like binding mode. Postprandial serum glucose peaks may be reduced by a mild peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic activity of leoligin. No effect on atherosclerotic plaque size was observed. As a non-toxic, cholesterol-, peak glucose-, and weight gain-lowering compound, leoligin continues to fulfil characteristics of a potential agent for the treatment of cardiovascular disease (CVD). The counterregulatory overexpression of hepatic HMGCR in leoligin treated animals possibly explains the missing permanent anti-atherosclerotic effect.
authors: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Bernhard
authors: B
authors: Scharinger
authors: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Barbara
authors: B
authors: Messner
authors: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Adrian
authors: A
authors: Türkcan
authors: Institute of Pharmacy/Pharmaceutical Chemistry and Centre for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innsbruck, Austria.
authors: Daniela
authors: D
authors: Schuster
authors: Institute of Pharmacy/Pharmaceutical Chemistry and Centre for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innsbruck, Austria.
authors: Anna
authors: A
authors: Vuorinen
authors: Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Florian
authors: F
authors: Pitterl
authors: Cardiac Surgery Research Laboratory, University Clinic for Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors: Katharina
authors: K
authors: Heinz
authors: Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Kathrin
authors: K
authors: Arnhard
authors: Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.
authors: Günther
authors: G
authors: Laufer
authors: Cardiac Surgery Research Laboratory, University Clinic for Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors: Michael
authors: M
authors: Grimm
authors: Institute of Pharmacy/Pharmacognosy and Centre for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innsbruck, Austria.
authors: Hermann
authors: H
authors: Stuppner
authors: Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Herbert
authors: H
authors: Oberacher
authors: Department of Internal Medicine, Intensive Care Unit, Medical University of Graz, Graz, Austria.
authors: Philipp
authors: P
authors: Eller
authors: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors: Andreas
authors: A
authors: Ritsch
authors: Cardiac Surgery Research Laboratory, University Clinic for Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: david.bernhard@i-med.ac.at.
authors: David
authors: D
authors: Bernhard
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006860:Hydrogen Bonding; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017705:Lignans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017705:Lignans; D047495:PPAR gamma; D010936:Plant Extracts; C542788:leoligin; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D005947:Glucose
keywords: Cholesterol; Diabetes; HMGCR inhibitor; Obesity; Therapy