scholarly journals The High Incidence of Valproate Hepatotoxicity in Infants May Relate to Familial Metabolic Defects

1990 ◽  
Vol 17 (2) ◽  
pp. 145-148 ◽  
Author(s):  
R.E. Appleton ◽  
K. Farrell ◽  
D.A. Applegarth ◽  
J.E. Dimmick ◽  
L.T.K. Wong ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Developmental Delay ◽  
Hepatic Failure ◽  
Metabolic Disorders ◽  
Acid Oxidation ◽  
Toxic Metabolite ◽  
Metabolic Defects ◽  
Intractable Seizures ◽  
High Incidence

ABSTRACT:The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.

scholarly journals Tang-Nai-Kang Alleviates Pre-diabetes and Metabolic Disorders and Induces a Gene Expression Switch toward Fatty Acid Oxidation in SHR.Cg-Leprcp/NDmcr Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0122024 ◽  
Author(s):  
Linyi Li ◽  
Hisae Yoshitomi ◽  
Ying Wei ◽  
Lingling Qin ◽  
Jingxin Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Disorders ◽  
Acid Oxidation

scholarly journals AMPK as a mediator of hormonal signalling

2009 ◽  
Vol 44 (2) ◽  
pp. 87-97 ◽  
Author(s):  
Chung Thong Lim ◽  
Blerina Kola ◽  
Márta Korbonits
Keyword(s):  
Protein Synthesis ◽  
Fatty Acid ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Metabolic Effects ◽  
Whole Body ◽  
Acid Oxidation ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Hormonal Signalling

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

Effects of valproic acid on cardiac metabolism

2004 ◽  
Vol 82 (10) ◽  
pp. 927-933 ◽  
Author(s):  
Thomas Daniels ◽  
Maureen Gallagher ◽  
George Tremblay ◽  
Robert L Rodgers
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Oxidation Rates ◽  
Coa Ligase ◽  
Rat Hearts ◽  
Chain Acyl ◽  
Oxidation Of Glucose

We investigated whether the antiepileptic valproic acid (VPA) might interfere with oxidative metabolism in heart, as it does in liver. We administered VPA to working rat hearts perfused with radiolabeled carbohydrate and fatty acid fuels. Measurements included oxidation rates of (i) glucose, pyruvate, or lactate in the presence of palmitate and (ii) palmitate, octanoate, or butyrate in the presence of glucose. Oxidation rates were quantified as the rate of appearance of14CO2or3H2O from14C- or3H-labeled substrates. In hearts perfused with palmitate, VPA (1 mmol/L) strongly inhibited the oxidation of pyruvate and lactate but slightly stimulated the oxidation of glucose. VPA also inhibited lactate or pyruvate uptake into erythrocytes in vitro. In hearts perfused with glucose, VPA strongly inhibited the oxidation of palmitate and octanoate but had no effect on butyrate oxidation. The absence of valproate CoA ligase activity in cell-free homogenates indicated that the inhibition of fatty acid oxidation by VPA did not require prior activation to valproyl-CoA. The results are consistent with the hypothesis that VPA selectively interferes with myocardial fuel oxidation by mechanisms that are independent of conversion to the CoA thioester.Key words: myocardial, glucose, lactate, pyruvate, palmitate, octanoate, butyrate, metabolism, medium-chain acyl-CoA ligase.

Impaired fatty acid oxidation in children on valproic acid and the effect of L-carnitine

Neurology ◽  
1993 ◽  
Vol 43 (11) ◽  
pp. 2362-2362 ◽  
Author(s):  
B. D. Kossak ◽  
E. Schmidt-Sommerfeld ◽  
D. A. Schoeller ◽  
P. Rinaldo ◽  
D. Penn ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Impaired Fatty Acid

scholarly journals Inhibition of fatty acid oxidation as a new target to treat Primary Amoebic Meningoencephalitis by repurposing two well-known drugs

2019 ◽  
Author(s):  
Maarten J. Sarink ◽  
Annelies Verbon ◽  
Aloysius G.M. Tielens ◽  
Jaap J. van Hellemond
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Amphotericin B ◽  
Fatty Acid Oxidation ◽  
New Drugs ◽  
Close Relative ◽  
Acid Oxidation ◽  
Healthy Children ◽  
Primary Amoebic Meningoencephalitis ◽  
Amoebic Meningoencephalitis

AbstractPrimary Amoebic Meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The disease mostly affects healthy children and young adults after contaminated water enters the nose, generally during recreational water activities. The amoeba migrate along the olfactory nerve to the brain, resulting in seizures, coma and eventually death. Previous research has shown that Naegleria gruberi, a close relative of N. fowleri, prefers lipids over glucose as an energy source. Therefore, we tested several inhibitors of fatty acid oxidation alongside the currently used drugs amphotericin B and miltefosine. Our data demonstrate that etomoxir, orlistat, perhexiline, thioridazine and valproic acid inhibited growth of N. gruberi. Furthermore, additive effects were seen when drugs were combined. Both thioridazine and valproic acid inhibit in vitro growth of N. gruberi in concentrations that can be obtained at the site of infection, which is doubtful with the currently used drugs amphotericin B and miltefosine. Both thioridazine and valproic acid have already been used for other diseases. As the development of new drugs and randomized controlled trials for this rare disease is nearly impossible, repurposing drugs is the most promising way to obtain additional drugs to combat PAM. Thioridazine and valproic acid are available drugs without major side-effects and can, therefore, be used as new complementary options in PAM therapy.

scholarly journals Evaluation of Metabolic Defects in Fatty Acid Oxidation Using Peripheral Blood Mononuclear Cells Loaded with Deuterium-Labeled Fatty Acids

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Miori Yuasa ◽  
Ikue Hata ◽  
Keiichi Sugihara ◽  
Yuko Isozaki ◽  
Yusei Ohshima ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Mononuclear Cells ◽  
Acid Oxidation ◽  
Peripheral Blood Mononuclear ◽  
Metabolic Defects ◽  
Diagnostic Indices ◽  
Blood Mononuclear Cells ◽  
Cycle Disorders

Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of β-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

2008 ◽  
Vol 31 (2) ◽  
pp. 205-216 ◽  
Author(s):  
M. F. B. Silva ◽  
C. C. P. Aires ◽  
P. B. M. Luis ◽  
J. P. N. Ruiter ◽  
L. IJlst ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

scholarly journals Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 8267
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Haoying Wu ◽  
Jun Yang ◽  
Jiangang Chen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Expression ◽  
Epoxide Hydrolase ◽  
Metabolic Disorders ◽  
Soluble Epoxide Hydrolase ◽  
Acid Oxidation ◽  
Serum Triglycerides ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Metabolic Protein

17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.

scholarly journals Peroxisome proliferator-activated receptor β/δ: a master regulator of metabolic pathways in skeletal muscle

2010 ◽  
Vol 4 (2) ◽  
Author(s):  
Shawon Lahiri ◽  
Walter Wahli
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Energy Expenditure ◽  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Therapeutic Interventions ◽  
Lipid Lowering ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

AbstractSkeletal muscle is considered to be a major site of energy expenditure and thus is important in regulating events affecting metabolic disorders. Over the years, both in vitro and in vivo approaches have established the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in fatty acid metabolism and energy expenditure in skeletal muscles. Pharmacological activation of PPARβ/δ by specific ligands regulates the expression of genes involved in lipid use, triglyceride hydrolysis, fatty acid oxidation, energy expenditure, and lipid efflux in muscles, in turn resulting in decreased body fat mass and enhanced insulin sensitivity. Both the lipid-lowering and the anti-diabetic effects exerted by the induction of PPARβ/δ result in the amelioration of symptoms of metabolic disorders. This review summarizes the action of PPARβ/δ activation in energy metabolism in skeletal muscles and also highlights the unexplored pathways in which it might have potential effects in the context of muscular disorders. Numerous preclinical studies have identified PPARβ/δ as a probable potential target for therapeutic interventions. Although PPARβ/δ agonists have not yet reached the market, several are presently being investigated in clinical trials.

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