TY - JOUR
T1 - Valproic acid is a novel activator of amp-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice
AU - Avery, Lindsay B.
AU - Bumpus, Namandjé N.
PY - 2014/1
Y1 - 2014/1
N2 - 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 ofmouse 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/obmice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and itsmetabolites as in vitro activators of AMPK.
AB - 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 ofmouse 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/obmice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and itsmetabolites as in vitro activators of AMPK.
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U2 - 10.1124/mol.113.089755
DO - 10.1124/mol.113.089755
M3 - Article
AN - SCOPUS:84890722029
SN - 0026-895X
VL - 85
SP - 1
EP - 10
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 1
ER -