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

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Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been reported that both n-3 and n-6 octadecatrienoic acids can increase hepatic fatty acid oxidation activity. It remains unclear, however, whether different enzymes in fatty acid oxidation show a similar response to n-3 and n-6 octadecatrienoic acids. The activity of hepatic fatty acid oxidation enzymes in rats fed an oil mixture rich in alpha-linolenic acid (18:3n-3) and borage oil rich in gamma-linolenic acid (18:3n-6) was therefore compared to that in rats fed an oil mixture rich in linoleic acid (18:2n-6) and a saturated fat (palm oil) in this study. Linseed oil served as the source of 18:3n-3 for the oil mixture rich in this octadecatrienoic acid and contained 30.6% 18:3n-3 but not 18:3n-6. Borage oil contained 25.7% 18:3n-6 and 4.5% 18:3n-3. Groups of seven rats each were fed diets containing 15% various fats for 15 d. The oxidation rate of palmitoyl-CoA in the peroxisomes was higher in rats fed a fat mixture rich in 18:3n-3 (3.03 nmol/min/mg protein) and borage oil (2.89 nmol/min/mg protein) than in rats fed palm oil (2.08 nmol/min/mg protein) and a fat mixture rich in 18:2n-6 (2.15 nmol/min/mg protein). The mitochondrial palmitoyl-CoA oxidation rate was highest in rats fed a fat mixture rich in 18:3n-3 (1.93 nmol/min/mg protein), but no significant differences in this parameter were seen among the other groups (1.25-1.46 nmol/min/mg protein). Compared to palm oil and fat mixtures rich in 18:2n-6, a fat mixture rich in 18:3n-3 and borage oil significantly increased the hepatic activity of carnitine palmitoyltransferase and acyl-CoA oxidase. Compared to palm oil and a fat mixture rich in 18:2n-6, a fat mixture rich in 18:3n-3, but not fats rich in 18:3n-6, significantly decreased 3-hydroxyacyl-CoA dehydrogenase activity. Compared to palm oil and a fat mixture rich in 18:2n-6, borage oil profoundly decreased mitochondrial acyl-CoA dehydrogenase activity, but a fat mixture rich in 18:3n-3 increased it. 2,4-Dienoyl-CoA reductase activity was significantly lower in rats fed palm oil than in other groups. Compared to other fats, borage oil significantly increased delt3,delta2-enoyl-CoA isomerase activity. Activity was also significantly higher in rats fed 18:2n-6 oil than in those fed palm oil. It was confirmed that both dietary 18:3n-6 and 18:3n-3 increased fatty acid oxidation activity in the liver. These two dietary octadecatrienoic acids differ considerably, however, in how they affect individual fatty acid oxidation enzymes.
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PMID:Comparative effects of alpha- and gamma-linolenic acids on rat liver fatty acid oxidation. 968 66

Among the many disorders of fatty acid beta-oxidation known today, the disorders of long-chain fatty acid oxidation are the most severe and life-threatening. One remarkable abnormality, not observed in, for instance, medium-chain acyl-CoA dehydrogenase deficiency, is the moderate to severe lactic acidaemia in long-chain fatty acid beta-oxidation-deficient patients, suggesting that oxidation of pyruvate is also compromised. In order to understand the underlying basis of the lactic acidaemia in these patients, we have studied the formation of L-lactate and pyruvate in cultured skin fibroblasts incubated with D-glucose. All long-chain fatty acid beta-oxidation-deficient cell lines studied were found to show a moderate elevation of lactate when compared with control and medium-chain acyl-CoA dehydrogenase-deficient fibroblasts. Interestingly, differences were found between cells deficient in long-chain 3-hydroxyacyl-CoA dehydrogenase and very-long-chain acyl-CoA dehydrogenase, suggesting that saturated acyl-CoA esters and their 3-hydroxyacyl-CoA derivatives affect pyruvate metabolism differently.
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PMID:Lactic acidosis in long-chain fatty acid beta-oxidation disorders. 976

The effects of sesamin, one of the most abundant lignans in sesame seed, on hepatic fatty acid oxidation were examined in rats that were fed experimental diets containing various amounts (0%, 0.1%, 0.2%, and 0.5%) of sesamin (a 1:1 mixture of sesamin and episesamin) for 15 days. Dietary sesamin dose-dependently increased both mitochondrial and peroxisomal palmitoyl-coenzyme A (CoA) oxidation rates. Mitochondrial activity almost doubled in rats on the 0.5% sesamin diet. Peroxisomal activity increased more than 10-fold in rats fed a 0.5% sesamin diet in relation to rats on the sesamin-free diet. Dietary sesamin greatly increased the hepatic activity of fatty acid oxidation enzymes, including carnitine palmitoyltransferase, acyl-CoA dehydrogenase, acyl-CoA oxidase, 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase. Dietary sesamin also increased the activity of 2,4-dienoyl-CoA reductase and delta3,delta2-enoyl-CoA isomerase, enzymes involved in the auxiliary pathway for beta-oxidation of unsaturated fatty acids dose-dependently. Examination of hepatic mRNA levels using specific cDNA probes showed a sesamin-induced increase in the gene expression of mitochondrial and peroxisomal fatty acid oxidation enzymes. Among these various enzymes, peroxisomal acyl-CoA oxidase and bifunctional enzyme gene expression were affected most by dietary sesamin (15- and 50-fold increase by the 0.5% dietary level). Sesamin-induced alterations in the activity and gene expression of carnitine palmitoyltransferase I and acyl-CoA oxidase were in parallel with changes in the mitochondrial and peroxisomal palmitoyl-CoA oxidation rate, respectively. In contrast, dietary sesamin decreased the hepatic activity and mRNA abundance of fatty acid synthase and pyruvate kinase, the lipogenic enzymes. However, this lignan increased the activity and gene expression of malic enzyme, another lipogenic enzyme. An alteration in hepatic fatty acid metabolism may therefore account for the serum lipid-lowering effect of sesamin in the rat.
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PMID:Sesamin, a sesame lignan, is a potent inducer of hepatic fatty acid oxidation in the rat. 1053 95

Inherited defects in myocardial long-chain fatty acid metabolism are increasingly recognized as a cause of cardiomyopathy and sudden death in children. To evaluate whether the phenotypic expression of these genetic diseases could be delineated using positron emission tomography (PET), 11 patients with inherited defects in fatty acid metabolism were evaluated and results were compared with those of 6 nonaffected siblings. Myocardial perfusion, myocardial oxygen consumption (MVO2), and long-chain fatty acid metabolism were determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO2 or plasma substrate levels between groups. Patients with defects in enzymes of fatty acid beta-oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase deficiencies) (n = 5) had diminished myocardial palmitate oxidation compared with healthy siblings (3.2 +/- 3.0 vs. 13.0 +/- 5.6 nmol/g per min, p < 0.03) and a decrease in the percentage of MVO2 accounted for by palmitate (2% +/- 3% vs. 9% +/- 5%, p < 0.04). In these patients, extracted palmitate was shunted into a slow-turnover compartment (predominantly reflecting esterification to triglycerides) with expansion of palmitate in that pool (185 +/- 246 compared with 27 +/- 67 nmol/g in healthy siblings,p < 0.02). In contrast, myocardium of patients with carnitine deficiency (n = 6) (all on oral carnitine therapy) had normal palmitate extraction but expansion of the interstitial/cytosolic fatty acid pool (617 +/- 399 vs. 261 +/- 73 nmol/g in healthy siblings, p < 0.04), suggesting different mechanisms for handling upstream fatty acyl intermediates. Thus, PET can be used to noninvasively assess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affected patients.
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PMID:Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy. 1176 85

Standardization of the nutritional care for patients with fatty-acid oxidation disorders is lacking. A literature review and national survey of metabolic dietitians describes the range of therapeutic strategies currently employed in the U.S. to treat patients with fatty-acid oxidation disorders. Questionnaire responses provided by dietitians specializing in metabolic disorders evaluated practices used for treatment of fatty acid oxidation disorders, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), and Trifunctional Protein deficiency (TFP). This survey reveals a significant lack of evidence supporting the protocols in use. Recent advances in tandem mass spectrometry technology promises an increase in the number of identified patients with fatty-acid oxidation disorders, which reinforces the need for comprehensive, clinical research studies to determine optimal care for patients with these genetic disorders.
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PMID:Management of fatty acid oxidation disorders: a survey of current treatment strategies. 1248 44

Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity. In this study, we examined the direct and indirect effects of leptin signaling on mitochondrial enzymes including those essential for peripheral fatty acid oxidation. We assessed the impact of leptin using the JCR:LA-cp rat, which lacks functional leptin receptors. The activities of marker mitochondrial enzymes citrate synthase (CS) and cytochrome oxidase (COX) were similar between wild-type (+/?) and corpulent (cp/cp) rats. In contrast, several tissues showed variations in the fatty acid oxidizing enzymes carnitine palmitoyltransferase II (CPT II), long-chain acyl-CoA dehydrogenase (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (HOAD). It was not clear if these changes were due to loss of leptin signaling or to insulin insensitivity. Consequently, we examined the effects of leptin on cultured C(2)C(12) and Sol8 cells. Leptin (3 days at 0, 0.2, or 2.0 nM) had no direct effect on the activities of CS, COX, or fatty acid oxidizing enzymes. Leptin treatment did not affect luciferase-based reporter genes under the control of transcription factors involved in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), nuclear respiratory factor-2 (NRF-2)) or fatty acid enzyme expression (peroxisome proliferator-activated receptors (PPARs)). These studies suggest that leptin exerts only indirect effects on mitochondrial gene expression in muscle, possibly arising from insulin resistance.
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PMID:Leptin and the control of respiratory gene expression in muscle. 1473 84

The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. RPE in culture possesses the machinery needed for mitochondrial fatty acid beta-oxidation in vitro. To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes. Human eye and brain sections were stained with antibodies to medium-chain (MCAD) and very long-chain acyl-CoA dehydrogenase (VLCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and mitochondrial trifunctional protein (MTP) harboring LCHAD. Antibodies to 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) and cytochrome c oxidase subunit I (COX I) were used as a reference. VLCAD, MTP, MCAD, SCHAD, MHBD, and COX I antibodies labeled most retinal layers and tissues of the human eye actively involved in oxidative metabolism (extraocular and intraocular muscle, the RPE, the corneal endothelium, and the ciliary epithelium). MTP and COX I antibodies labeled the inner segments of photoreceptors. The choriocapillaris was labeled only with SCHAD and MCAD antibodies. In the brain, the choroid plexus and nuclei of the brain stem were most intensely labeled with beta-oxidation antibodies, whereas COX I antibodies strongly labeled neurons in several regions of the brain. Mitochondrial fatty acid beta-oxidation likely plays a role in ocular energy production in vivo. The RPE rather than the choriocapillaris could be the critical affected cell layer in LCHAD retinopathy. Reduced energy generation in the choroid plexus may contribute to the cerebral edema observed in patients with beta-oxidation defects.
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PMID:Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. 1534 68

In the present paper, we describe a novel method which enables the analysis of tissue acylcarnitines and carnitine biosynthesis intermediates in the same sample. This method was used to investigate the carnitine and fatty acid metabolism in wild-type and LCAD-/- (long-chain acyl-CoA dehydrogenase-deficient) mice. In agreement with previous results in plasma and bile, we found accumulation of the characteristic C14:1-acylcarnitine in all investigated tissues from LCAD-/- mice. Surprisingly, quantitatively relevant levels of 3-hydroxyacylcarnitines were found to be present in heart, muscle and brain in wild-type mice, suggesting that, in these tissues, long-chain 3-hydroxyacyl-CoA dehydrogenase is rate-limiting for mitochondrial beta-oxidation. The 3-hydroxyacylcarnitines were absent in LCAD-/- tissues, indicating that, in this situation, the beta-oxidation flux is limited by the LCAD deficiency. A profound deficiency of acetylcarnitine was observed in LCAD-/- hearts, which most likely corresponds with low cardiac levels of acetyl-CoA. Since there was no carnitine deficiency and only a marginal elevation of potentially cardiotoxic acylcarnitines, we conclude from these data that the cardiomyopathy in the LCAD-/- mouse is caused primarily by a severe energy deficiency in the heart, stressing the important role of LCAD in cardiac fatty acid metabolism in the mouse.
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PMID:Characterization of carnitine and fatty acid metabolism in the long-chain acyl-CoA dehydrogenase-deficient mouse. 1553 1

Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.
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PMID:Long-chain fatty acid oxidation during early human development. 1584 37

We recently reported the expression and activity of several fatty acid oxidation enzymes in human embryonic and fetal tissues including brain and spinal cord. Liver and heart showed expression of both very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) mRNA. However, while mRNA expression of LCHAD could be clearly detected in the retina and spinal cord, expression of VLCAD mRNA was low to undetectable in these tissues. Nevertheless, abundant acyl-CoA dehydrogenase (ACAD) activity was detected with palmitoyl-CoA as substrate in fetal central nervous tissue. These conflicting data suggested the presence of a different long-chain ACAD in human embryonic and fetal brain. In this study, using in situ hybridization as well as enzymatic studies, we identified acyl-CoA dehydrogenase 9 (ACAD 9) as the long-chain ACAD in human embryonic and fetal central nervous tissue. Until now, no clinical signs and symptoms of central nervous system involvement have been reported in VLCAD deficiency. A novel long-chain FAO defect, i.e., ACAD 9 deficiency with only central nervous system involvement, could, if not lethal during intra uterine development, easily escape proper diagnosis, since probably no classical signs and symptoms of FAO deficiency will be observed. Screening for ACAD 9 deficiency in patients with undefined neurological symptoms and/or impairment in neurological development of unknown origin is necessary to establish if ACAD 9 deficiency exists as a separate disease entity.
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PMID:Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain. 1675 Jan 64


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