title: Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts.
abstract: BACKGROUND
  Inborn enzyme defects of mitochondrial fatty acid beta-oxidation (FAO) form a large group of genetic disorders associated to variable clinical presentations ranging from life-threatening pediatric manifestations up to milder late onset phenotypes, including myopathy. Very few candidate drugs have been identified in this group of disorders. Resveratrol (RSV) is a natural polyphenol with anti-oxidant and anti-inflammatory effects, recently shown to have beneficial metabolic properties in mice models. Our study explores its possible effects on FAO and mitochondrial energy metabolism in human cells, which are still very little documented.
  
  
  METHODS
  Using cells from controls and from patients with Carnitine Palmitoyl Transferase 2 (CPT2) or Very Long Chain AcylCoA Dehydrogenase (VLCAD) deficiency we characterized the metabolic effects of RSV, RSV metabolites, and other stilbenes. We also focused on analysis of RSV uptake, and on the effects of low RSV concentrations, considering the limited bioavailability of RSV in vivo.
  
  
  RESULTS
  Time course of RSV accumulation in fibroblasts over 48 h of treatment were consistent with the resulting stimulation or correction of FAO capacities. At 48 h, half maximal and maximal FAO stimulations were respectively achieved for 37,5 microM (EC50) and 75 microM RSV, but we found that serum content of culture medium negatively modulated RSV uptake and FAO induction. Indeed, decreasing serum from 12% to 3% led to shift EC50 from 37,5 to 13 microM, and a 2.6-3.6-fold FAO stimulation was reached with 20 microM RSV at 3% serum, that was absent at 12% serum. Two other stilbenes often found associated with RSV, i.e. cis- RSV and piceid, also triggered significant FAO up-regulation. Resveratrol glucuro- or sulfo- conjugates had modest or no effects. In contrast, dihydro-RSV, one of the most abundant circulating RSV metabolites in human significantly stimulated FAO (1.3-2.3-fold).
  
  
  CONCLUSIONS
  This study provides the first compared data on mitochondrial effects of resveratrol, its metabolites, and other natural compounds of the stilbene family in human cells. The results clearly indicate that several of these compounds can improve mitochondrial FAO capacities in human FAO-deficient cells.
authors.forename: Virginie
authors.initials: V
authors.lastname: Aires
authors.forename: Dominique
authors.initials: D
authors.lastname: Delmas
authors.forename: Carole
authors.initials: C
authors.lastname: Le Bachelier
authors.forename: Norbert
authors.initials: N
authors.lastname: Latruffe
authors.forename: Dimitri
authors.initials: D
authors.lastname: Schlemmer
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
authors.affiliation: INSERM UMR-S 1124, Université Paris Descartes, UFR Biomédicale des Saints-Pères, 45, rue des Saints-Pères, 75270 Paris cedex 06, France. jean.bastin@inserm.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
mesh_terms: D015153:Blotting, Western; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D013267:Stilbenes; D000077185:Resveratrol