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

Abstract 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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Sabine Gerbal-Chaloin, Claire Gondeau, Dang-Nghiem Vo, Sana Belkahla, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Milica Bozic, Jose M. Valdivielso, Fabienne Bejjani, Isabelle Jariel, Isabel C. Lopez-Mejia, Lluis Fajas, Charles-Henri Lecellier, Javier Hernandez, Martine Daujat, Martin Villalba
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5f3afc8b38a14bb08f1bfec74537c804
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5f3afc8b38a14bb08f1bfec74537c804
record_format	dspace
spelling	oai:doaj.org-article:5f3afc8b38a14bb08f1bfec74537c8042021-12-02T15:05:23ZThe PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway10.1038/s41598-017-10339-52045-2322https://doaj.org/article/5f3afc8b38a14bb08f1bfec74537c8042017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-10339-5https://doaj.org/toc/2045-2322Abstract 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.Abrar Ul Haq KhanNerea Allende-VegaDelphine GitenaySabine Gerbal-ChaloinClaire GondeauDang-Nghiem VoSana BelkahlaStefania OrecchioniGiovanna TalaricoFrancesco BertoliniMilica BozicJose M. ValdivielsoFabienne BejjaniIsabelle JarielIsabel C. Lopez-MejiaLluis FajasCharles-Henri LecellierJavier HernandezMartine DaujatMartin VillalbaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abrar Ul Haq Khan Nerea Allende-Vega Delphine Gitenay Sabine Gerbal-Chaloin Claire Gondeau Dang-Nghiem Vo Sana Belkahla Stefania Orecchioni Giovanna Talarico Francesco Bertolini Milica Bozic Jose M. Valdivielso Fabienne Bejjani Isabelle Jariel Isabel C. Lopez-Mejia Lluis Fajas Charles-Henri Lecellier Javier Hernandez Martine Daujat Martin Villalba The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
description	Abstract 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.
format	article
author	Abrar Ul Haq Khan Nerea Allende-Vega Delphine Gitenay Sabine Gerbal-Chaloin Claire Gondeau Dang-Nghiem Vo Sana Belkahla Stefania Orecchioni Giovanna Talarico Francesco Bertolini Milica Bozic Jose M. Valdivielso Fabienne Bejjani Isabelle Jariel Isabel C. Lopez-Mejia Lluis Fajas Charles-Henri Lecellier Javier Hernandez Martine Daujat Martin Villalba
author_facet	Abrar Ul Haq Khan Nerea Allende-Vega Delphine Gitenay Sabine Gerbal-Chaloin Claire Gondeau Dang-Nghiem Vo Sana Belkahla Stefania Orecchioni Giovanna Talarico Francesco Bertolini Milica Bozic Jose M. Valdivielso Fabienne Bejjani Isabelle Jariel Isabel C. Lopez-Mejia Lluis Fajas Charles-Henri Lecellier Javier Hernandez Martine Daujat Martin Villalba
author_sort	Abrar Ul Haq Khan
title	The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
title_short	The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
title_full	The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
title_fullStr	The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
title_full_unstemmed	The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway
title_sort	pdk1 inhibitor dichloroacetate controls cholesterol homeostasis through the erk5/mef2 pathway
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/5f3afc8b38a14bb08f1bfec74537c804
work_keys_str_mv	AT abrarulhaqkhan thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT nereaallendevega thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT delphinegitenay thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT sabinegerbalchaloin thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT clairegondeau thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT dangnghiemvo thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT sanabelkahla thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT stefaniaorecchioni thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT giovannatalarico thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT francescobertolini thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT milicabozic thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT josemvaldivielso thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT fabiennebejjani thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT isabellejariel thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT isabelclopezmejia thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT lluisfajas thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT charleshenrilecellier thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT javierhernandez thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT martinedaujat thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT martinvillalba thepdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT abrarulhaqkhan pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT nereaallendevega pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT delphinegitenay pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT sabinegerbalchaloin pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT clairegondeau pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT dangnghiemvo pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT sanabelkahla pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT stefaniaorecchioni pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT giovannatalarico pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT francescobertolini pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT milicabozic pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT josemvaldivielso pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT fabiennebejjani pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT isabellejariel pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT isabelclopezmejia pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT lluisfajas pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT charleshenrilecellier pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT javierhernandez pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT martinedaujat pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway AT martinvillalba pdk1inhibitordichloroacetatecontrolscholesterolhomeostasisthroughtheerk5mef2pathway
_version_	1718388832471089152

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

Ejemplares similares