Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.4.1.2 (
acetyl-CoA carboxylase
)
2,876
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. 2410 77
