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Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts

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 d...

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Autores principales: Aires, Virginie, Delmas, Dominique, Le Bachelier, Carole, Latruffe, Norbert, Schlemmer, Dimitri, Benoist, Jean-François, Djouadi, Fatima, Bastin, Jean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051957/
https://www.ncbi.nlm.nih.gov/pubmed/24898617
http://dx.doi.org/10.1186/1750-1172-9-79
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author Aires, Virginie
Delmas, Dominique
Le Bachelier, Carole
Latruffe, Norbert
Schlemmer, Dimitri
Benoist, Jean-François
Djouadi, Fatima
Bastin, Jean
author_facet Aires, Virginie
Delmas, Dominique
Le Bachelier, Carole
Latruffe, Norbert
Schlemmer, Dimitri
Benoist, Jean-François
Djouadi, Fatima
Bastin, Jean
author_sort Aires, Virginie
collection PubMed
description 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.
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spelling pubmed-40519572014-06-12 Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts Aires, Virginie Delmas, Dominique Le Bachelier, Carole Latruffe, Norbert Schlemmer, Dimitri Benoist, Jean-François Djouadi, Fatima Bastin, Jean Orphanet J Rare Dis Research 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. BioMed Central 2014-06-05 /pmc/articles/PMC4051957/ /pubmed/24898617 http://dx.doi.org/10.1186/1750-1172-9-79 Text en Copyright © 2014 Aires et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Aires, Virginie
Delmas, Dominique
Le Bachelier, Carole
Latruffe, Norbert
Schlemmer, Dimitri
Benoist, Jean-François
Djouadi, Fatima
Bastin, Jean
Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title_full Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title_fullStr Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title_full_unstemmed Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title_short Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
title_sort stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051957/
https://www.ncbi.nlm.nih.gov/pubmed/24898617
http://dx.doi.org/10.1186/1750-1172-9-79
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