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Título:
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The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
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Autor/a:
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Khan, Abrar Ul Haq; Allende-Vega, Nerea; Gitenay, Delphine; Gerbal-Chaloin, Sabine; Gondeau, Claire; Vo, Dang-Nghiem; Belkahla, Sana; Orecchioni, Stefania; Talarico, Giovanna; Bertolini, Francesco; Bozić Stanojević, Milica; Valdivielso Revilla, José Manuel; Bejjani, Fabienne; Jariel, Isabelle; Lopez-Mejia, Isabel C.; Fajas, Lluis; Lecellier, Charles-Henri; Hernandez, Javier; Daujat, Martine; Villalba, Martin
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Notas:
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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.
This work was supported by a grant from Fondation de France (0057921), fellowship from the Higher Education Commission, Pakistan (AK) and fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche (MESR) (DNV). |
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Derechos:
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cc-by (c) Khan, Abrar Ul Haq et al., 2017
http://creativecommons.org/licenses/by/3.0/es
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Tipo de documento:
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Artículo
Artículo - Versión publicada |
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Editor:
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Nature Publishing Group
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