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Research ArticleArticle

Valproic Acid Is a Novel Activator of AMP-Activated Protein Kinase and Decreases Liver Mass, Hepatic Fat Accumulation, and Serum Glucose in Obese Mice

Lindsay B. Avery and Namandjé N. Bumpus
Molecular Pharmacology January 2014, 85 (1) 1-10; DOI: https://doi.org/10.1124/mol.113.089755
Lindsay B. Avery
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Namandjé N. Bumpus
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract

Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of epilepsy. Here we demonstrate that VPA is a novel activator of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism, using primary mouse and human hepatocytes. Incubation of primary mouse hepatocytes with VPA resulted in increased levels of phosphorylated AMPK and acetyl-CoA carboxylase (ACC). This finding was recapitulated using primary human hepatocytes. Pretreatment of mouse hepatocytes with a small-molecule inhibitor of AMPK, Compound C (6-​[4-​(2-​piperidin-​1-​ylethoxy)​phenyl]​-​3-​pyridin-​4-​ylpyrazolo[1,5-​a]​pyrimidine), abrogated the phosphorylation of ACC following treatment with VPA. The cytochrome P450 inhibitor 1-aminobenzotriazole blocked the VPA-stimulated phosphorylation of AMPK, suggesting a requirement for biotransformation of VPA. In line with this, treatment of hepatocytes with metabolites of VPA resulted in increased phosphorylation of AMPK/ACC as compared with VPA. Treatment of ob/ob mice with VPA for 14 days resulted in decreased liver masses, hepatic fat accumulation, and serum glucose. These results paralleled those observed in mice treated with metformin. In addition, a targeted mass spectrometry–based metabolomics assay revealed several small molecules that were differentially abundant in the serum of ob/ob mice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and its metabolites as in vitro activators of AMPK.

Footnotes

    • Received September 18, 2013.
    • Accepted October 8, 2013.
  • This work was supported by the National Institutes of Health [Grant R01GM103853].

  • dx.doi.org/10.1124/mol.113.089755.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (1)
Molecular Pharmacology
Vol. 85, Issue 1
1 Jan 2014
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Research ArticleArticle

Valproic Acid and Metabolites Activate AMPK

Lindsay B. Avery and Namandjé N. Bumpus
Molecular Pharmacology January 1, 2014, 85 (1) 1-10; DOI: https://doi.org/10.1124/mol.113.089755

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Research ArticleArticle

Valproic Acid and Metabolites Activate AMPK

Lindsay B. Avery and Namandjé N. Bumpus
Molecular Pharmacology January 1, 2014, 85 (1) 1-10; DOI: https://doi.org/10.1124/mol.113.089755
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