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

Avery, Lindsay B.; Bumpus, Namandjé N.

doi:10.1124/mol.113.089755

Cited by 49 publications

(36 citation statements)

References 32 publications

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“…Several studies revealed the activation of AMPK related signaling pathway with non-specific HDAC inhibitors, MPT0E014 and VPA, in both type 1 diabetic rats and obese mice with several other metabolic variables (58, 60). However, the effect of the HDAC3 inhibitor on AMPK in the diabetic heart remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

et al. 2017

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Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevent DCM. Type 1 diabetes OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then sacrificed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice sacrificed immediately or 3 months later following the three-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two-time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. This study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.

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Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

et al. 2017

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“…A previous study reported the integration of metabolite levels of bio fluids and other biochemical information (e.g., glucose and HbA1c) could better reflect T2DM risk than a single established risk factor [29,[39][40][41][42][43][44][45][46]. Determination of the levels of several amino acid and other metabolites that showed a marked change after metformin treatment could significantly improve drug response prediction and serve as markers for the diagnosis of T2DM.…”

Section: Discussionmentioning

confidence: 99%

Mechanism by which Metformin Influence Metabolic Changes in Human: A Systematic-Review

Park¹,

Kim²,

Shin³

2016

J Diabetes Metab

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Metformin is the most widely used oral antihyperglycemic agent for the improvement of type 2 diabetes mellitus (T2DM). In patients with T2DM, metformin increases insulin sensitivity and reduces glucose production. In this systematic review, we identified and compared metabolic changes induced by metformin administration.We searched articles published within the past 5 years on Pubmed.gov by using the keywords "metformin and metabolomics." No restrictions were placed on the languages, species, or gender during the selection of articles. From the 29 identified articles, we excluded non-human in vivo or in vitro studies, studies in cancer patients, and studies in which the focus was not on variation in the levels of metabolites after administration of medication such as pharmacogenetic studies. Finally, we selected 8 articles and compared their results.In the selected study results, a treatment with metformin and a combination of metformin and other anti-diabetic agents decreased the levels of phenylalanine, tyrosine, lysine, and glutamate to 5.58 ± 2.23%, 11.50 ± 2.12%, 25.28 ± 27.90%, and 35.49 ± 26.18% (mean ± SD), respectively, but increased the levels of alanine to 16.00% in 3 months-5 years of follow-up after metformin treatment compared to the control. The levels of total cholesterol and low-density lipoprotein (LDL) cholesterol (5.28%) decreased, whereas those of high-density lipoprotein (HDL) cholesterol increased by 34.65% in 18-30 months of follow-up after administration of metformin.Metformin administration in human alters the blood concentration of phenylalanine, tyrosine, glutamate and lysine. Further confirmatory studies are required to understand how these metabolites related to the drug mechanism and also drug response, and to develop the biomarkers for predicting metformin response in humans.

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“…119 Valproic acid, a potent antiepileptic agent, is effective in activating AMPK in vitro and in vivo. 120 Treatment of Lep ob/ob hyperphagic obese mice with valproic acid significantly reduced plasma glucose levels and decreased both liver mass and fat content, owing to AMPK activation. 120 Further studies will need to be conducted to define the role of these agents in activating AMPK in different stages of CKD.…”

Section: Mitochondrial Biogenesis and Kidney Diseasementioning

confidence: 98%

Novel targets of antifibrotic and anti-inflammatory treatment in CKD

2014

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Chronic kidney disease (CKD) is becoming a worldwide epidemic, driven largely by the dramatic rise in the prevalence of diabetes and obesity. Novel targets and treatments for CKD are, therefore, desperately needed—to both mitigate the burden of this disease in the general population and reduce the necessity for renal replacement therapy in individual patients. This Review highlights new insights into the mechanisms that contribute to CKD, and approaches that might facilitate the development of disease-arresting therapies for CKD. Particular focus is given to therapeutic approaches using antifibrotic agents that target the transforming growth factor β superfamily. In addition, we discuss new insights regarding the roles of vascular calcification, the NADPH oxidase family, and inflammation in the pathogenesis of CKD. We also highlight a new understanding regarding kidney energy sensing pathways (AMPK, sirtuins, and mTOR) in a variety of kidney diseases and how they are linked to inflammation and fibrosis. Finally, exciting new insights have been made into the role of mitochondrial function and mitochondrial biogenesis in relation to progressive kidney disease. Prospective therapeutics based on these findings will hopefully renew hope for clinicians and patients in the near future.

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

Cited by 49 publications

References 32 publications

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Mechanism by which Metformin Influence Metabolic Changes in Human: A Systematic-Review

Novel targets of antifibrotic and anti-inflammatory treatment in CKD

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