The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
| Autor: | 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, Bozic, Milica, Valdivielso, Jose M., Bejjani, Fabienne, Jariel, Isabelle, Lopez-Mejia, Isabel C., Fajas, Lluis, Lecellier, Charles-Henri, Hernandez, Javier, Daujat, Martine, Villalba, Martin |
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| Přispěvatelé: | Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), European Institute of Oncology [Milan] (ESMO), Universitat de Lleida, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Philips, Alexandre, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Université de Montpellier (UM), Physiopathologie hépatique, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Haematology-Oncology [Milan, Italy] (Department of Medicine), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), IK4-Ideko, IK4-Ideko-IK4-Ideko |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Cell Survival
Science Protein Serine-Threonine Kinases [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Article Mice Cell Line Tumor Animals Homeostasis ComputingMilieux_MISCELLANEOUS Mitogen-Activated Protein Kinase 7 Dichloroacetic Acid MEF2 Transcription Factors Pyruvate Dehydrogenase Acetyl-Transferring Kinase [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology 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 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 Lipid Metabolism Cholesterol Receptors LDL Hepatocytes Medicine lipids (amino acids peptides and proteins) Reactive Oxygen Species Signal Transduction |
| Zdroj: | Scientific Reports Recercat. Dipósit de la Recerca de Catalunya instname Scientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) Scientific Reports, 2017, 7 (1), ⟨10.1038/s41598-017-10339-5⟩ Scientific Reports, Nature Publishing Group, 2017, 7 (1), ⟨10.1038/s41598-017-10339-5⟩ Scientific reports, vol. 7, no. 1, pp. 10654 Repositorio Abierto de la UdL Universitad de Lleida |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-10339-5⟩ |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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