ArticleScientific reports2017
The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 36 citations in OpenAlex.
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- Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives.Cells · 2026Review
- Dichloroacetate enhances Chemo-sensitivity in wild-type P53 breast cancer cells by modulating ABCG2 and NKG2DL.Scientific reports · 2025Article
- Review
- Regulatory effect of Wnt signaling on mitochondria in cancer: from mechanism to therapy.Apoptosis : an international journal on programmed cell death · 2025Review
- Effect and mechanism of Dichloroacetate in the treatment of stroke and the resolution strategy for side effect.European journal of medical research · 2025Review
- Is the MAPK ERK5 the nexus from FAO to NK cell-mediated metastasis immune surveillance?Frontiers in immunology · 2025Review
- Bone and Extracellular Signal-Related Kinase 5 (ERK5).Biomolecules · 2024Review
- Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer.Molecular medicine (Cambridge, Mass.) · 2024Article
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- Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk.Cardiovascular research · 2023Article
- Metabolic shift towards oxidative phosphorylation reduces cell-density-induced cancer-stem-cell-like characteristics in prostate cancer in vitro.Biology open · 2023Article
- Analysis of a genetic region affecting mouse body weight.Physiological genomics · 2023Article
- Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.Nature communications · 2023Article
- ATP8B1 Deficiency Results in Elevated Mitochondrial Phosphatidylethanolamine Levels and Increased Mitochondrial Oxidative Phosphorylation in Human Hepatoma Cells.International journal of molecular sciences · 2022Article
- Article
- Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities.International journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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