The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.

Détails

Ressource 1Télécharger: s41598-017-10339-5.pdf (2375.58 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_067DA1C10A2D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.
Périodique
Scientific reports
Auteur(s)
Khan AUH, Allende-Vega N., Gitenay D., Gerbal-Chaloin S., Gondeau C., Vo D.N., Belkahla S., Orecchioni S., Talarico G., Bertolini F., Bozic M., Valdivielso J.M., Bejjani F., Jariel I., Lopez-Mejia I.C., Fajas L., Lecellier C.H., Hernandez J., Daujat M., Villalba M.
ISSN
2045-2322 (Electronic)
ISSN-L
2045-2322
Statut éditorial
Publié
Date de publication
06/09/2017
Peer-reviewed
Oui
Volume
7
Numéro
1
Pages
10654
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development.
Mots-clé
Animals, Cell Line, Tumor, Cell Survival/drug effects, Cholesterol/metabolism, Dichloroacetic Acid/pharmacology, Hepatocytes/drug effects, Hepatocytes/metabolism, Homeostasis/drug effects, Lipid Metabolism/drug effects, MEF2 Transcription Factors/metabolism, Mice, Mitogen-Activated Protein Kinase 7/metabolism, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Reactive Oxygen Species/metabolism, Receptors, LDL/genetics, Receptors, LDL/metabolism, Signal Transduction/drug effects
Pubmed
Web of science
Open Access
Oui
Création de la notice
29/09/2017 9:41
Dernière modification de la notice
20/08/2019 13:28
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