serval:BIB_067DA1C10A2D
The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.
10.1038/s41598-017-10339-5
000409439900072
28878225
Khan
AUH
author
Allende-Vega
N.
author
Gitenay
D.
author
Gerbal-Chaloin
S.
author
Gondeau
C.
author
Vo
D.N.
author
Belkahla
S.
author
Orecchioni
S.
author
Talarico
G.
author
Bertolini
F.
author
Bozic
M.
author
Valdivielso
J.M.
author
Bejjani
F.
author
Jariel
I.
author
Lopez-Mejia
I.C.
author
Fajas
L.
author
Lecellier
C.H.
author
Hernandez
J.
author
Daujat
M.
author
Villalba
M.
author
article
2017-09-06
Scientific reports
2045-2322
2045-2322
journal
7
1
10654
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
University of Lausanne
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