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:1.3.1.8 (acyl-CoA dehydrogenase)
785 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In pressure overload-induced hypertrophy, the heart increases its reliance on glucose as a fuel while decreasing fatty acid oxidation. A key regulator of this substrate switching in the hypertrophied heart is peroxisome proliferator-activated receptor alpha (PPARalpha). We tested the hypothesis that down-regulation of PPARalpha is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPARalpha. Pressure overload (induced by constriction of the ascending aorta for 7 days in rats) resulted in cardiac hypertrophy, increased expression of fetal genes (atrial natriuretic factor and skeletal alpha-actin), decreased expression of PPARalpha and PPARalpha-regulated genes (medium chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase 4), and caused substrate switching (measured ex vivo in the isolated working heart preparation). Treatment of rats with the specific PPARalpha agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPARalpha activation blocked skeletal alpha-actin induction, reversed the down-regulation of measured PPARalpha-regulated genes in the hypertrophied heart, and prevented substrate switching. This PPARalpha reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo). Thus, PPARalpha down-regulation is essential for the maintenance of contractile function of the hypertrophied heart.
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PMID:Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. 1157 33

In a previous report, we observed an altered proportion of fiber types and a reduction of capillary per fiber ratio in extensor digitorus longus (EDL) and soleus (SOL) muscles of deoxicorticosterone acetate (DOCA)-salt hypertensive rats when compared with controls. The aim of the present study was to ascertain various carbohydrate and lipid enzyme activities and substrates that may be involved in the morphological changes reported. In the SOL muscle of hypertensive rats, glucose, glycogen and triglycerides (TG) levels were increased, citrate synthase (CS) and beta-hydroxy-acyl-CoA dehydrogenase (HAD) activities were reduced, while hexokinase (HK) and lipoprotein lipase (LPL), LPL mass, lactate and free fatty acids (FFA) levels were unchanged. In EDL muscles of hypertensive rats, glycogen levels and LPL mass were higher than in controls, while CS, HAD, HK, and LPL activities and glucose, lactate, FFA and TG levels were unmodified. Serum levels of insulin, TG, cholesterol and FFA were increased while glucose levels were decreased and high-density lipoprotein-cholesterol levels were similar in hypertensive rats when compared with controls. In conclusion, hypertensive rats showed increased glycogen in both EDL and SOL muscles, with hyperinsulinemia and reduced glycemia. Hyperinsulinemia might have been a compensatory response to insulin resistance. The oxidative capacity of SOL muscle was reduced indicating that glucose uptake was conduced via non-oxidative metabolism. TG, FFA and cholesterol were increased in serum and TG in SOL muscle.
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PMID:Metabolic changes in DOCA-salt hypertensive rats. 1191 12

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of fatty acid beta-oxidation and presents acutely with hypoglycemia, or a Reye-like illness with low free carnitine, often provoked by an infection or an excessive period of fasting. After acute attack these children are for the most time asymptomatic and may have normal plasma free carnitine concentrations. We observed a regularity in time course of serum free carnitine concentration during two attacks of Reye-like illness in patient with MCAD deficiency. Molecular investigation confirmed that the patient was homozygote for A985G mutation. Free carnitine was measured by enzymatic UV-test. First attack of severe hypoglycemia and Reye-like symptoms started at the age of 15 months and the second at the age of 25 months. In both episodes, treatment with intravenous glucose was given immediately, but without carnitine supplementation. Between the attacks patient was on a normal diet. In both attacks, low serum free carnitine concentration from the time of acute attack continually decreased for up to 8-13 days and then normalized at about 25 days after attack. We think that the time course of serum free carnitine may help in knowledge about carnitine depletion in MCAD deficiency. This is the first observation of this pattern during an acute attack and needs to be confirmed by other patients with MCAD deficiency. (Fig. 2, Ref. 7.).
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PMID:Serum free carnitine in medium chain acyl-CoA dehydrogenase deficiency. 1505 33

It is demonstrated that crotonyl-CoA reductase (CCR) plays a significant role in providing methylmalonyl-CoA for monensin biosynthesis in oil-based 10-day fermentations of Streptomyces cinnamonensis. Under these conditions S. cinnamonensis L1, a derivative of a high-titre producing industrial strain C730.1 in which ccr has been insertionally inactivated, produces only 15 % of the monensin yield. Labelling of the coenzyme A pools using [3H]-beta-alanine and analysis of intracellular acyl-CoAs in the L1 and C730.1 strains demonstrated that loss of ccr led to lower levels of the monensin precursor methymalonyl-CoA, relative to coenzyme A. Expression of a heterologous ccr gene from Streptomyces collinus fully restored monensin production to the L1 mutant. Using C730.1 and an oil-based extended fermentation an exceptionally efficient and comparably intact incorporation of ethyl [3,4-13C2]acetoacetate into both the ethylmalonyl-CoA- and methylmalonyl-CoA-derived positions of monensin was observed. No labelling of the malonyl-CoA-derived positions was observed. The opposite result was observed when the incorporation study was carried out with the L1 strain, demonstrating that ccr insertional inactivation has led to a reversal of carbon flux from an acetoacetyl-CoA intermediate. These results dramatically contrast similar analyses of the L1 mutant in glucose-soybean medium which indicate a role in providing ethylmalonyl-CoA but not methylmalonyl-CoA, thus causing a change in the ratio of monensin A and monensin B analogues, but not the overall monensin titre. These results demonstrate that the relative contributions of different pathways and enzymes to providing polyketide precursors are thus dependent upon the fermentation conditions. Furthermore, the generally accepted pathways for providing methylmalonyl-CoA for polyketide production may not be significant for the S. cinnamonensis high-titre monensin producer in oil-based extended fermentations. An alternative pathway, leading from the fatty acid catabolite acetyl-CoA, via the CCR-catalysed reaction is proposed.
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PMID:Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation. 1547 Jan 23

The effect of dietary starch and fat content on serum creatine kinase (CK) activity and substrate availability was evaluated in 4 mares of Quarter Horse-related breeds with polysaccharide storage myopathy (PSSM). Four isocaloric diets ranging in digestible energy (DE) from 21.2% (diet A), 14.8% (B), 8.4% (C), to 3.9% (D) for starch, and 7.2% DE (diet A), 9.9% (B), to 12.7% DE (diet C and D) for fat were fed for 6-week periods (4 weeks with exercise) using a 4 X 4 Latin square design. Postprandial glucose and insulin responses were measured, and 4 hours postexercise, serum CK activity, glucose, insulin, free fatty acids (FFA), and beta-hydroxybutyrate (beta-HBA) were analyzed. Glycogen, glucose-6-phosphate, citrate synthase, 3-hydroxy-acyl-CoA dehydrogenase, lactate dehydrogenase as well as abnormal polysaccharide and lipid content were measured in middle gluteal muscle samples. Postprandial insulin and glucose response was higher for diet A versus D. Log CK activity was higher with diets A, B, and C versus D. Daily insulin was higher and FFA lower on diet A versus B, C, and D, whereas glucose varied only slightly with diet. Muscle oxidative capacity and lipid stores were low in PSSM horses and muscle glycogen and abnormal polysaccharide content high on both diets A and D. Individual variation occurred in the response of PSSM horses to diets differing in starch and fat content. However, for those horses with clinical manifestations of PSSM, a diet with <5% DE starch and >12% DE fat can reduce exertional rhabdomyolysis, potentially by increasing availability of FFA for muscle metabolism.
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PMID:The effect of varying dietary starch and fat content on serum creatine kinase activity and substrate availability in equine polysaccharide storage myopathy. 1563 74

The heart utilizes primarily fatty acids for energy production. During ischemia, however, diminished oxygen supply necessitates a switch from beta-oxidation of fatty acids to glucose utilization and glycolysis. Molecular mechanisms responsible for these alterations in metabolism are not fully understood. Mitochondrial acyl-CoA dehydrogenase catalyzes the first committed step in the beta-oxidation of fatty acids. In the current study, an in vivo rat model of myocardial ischemia was utilized to determine whether specific acyl-CoA dehydrogenases exhibit ischemia-induced alterations in activity, identify mechanisms responsible for changes in enzyme function, and assess the effects on mitochondrial respiration. Very long chain acyl-CoA dehydrogenase (VLCAD) activity declined 34% during 30 min of ischemia. Loss in activity appeared specific to VLCAD as medium chain acyl-CoA dehydrogenase activity remained constant. Loss in VLCAD activity during ischemia was not due to loss in protein content. In addition, activity was restored in the presence of the detergent Triton X-100, suggesting that changes in the interaction between the protein and inner mitochondrial membrane are responsible for ischemia-induced loss in activity. Palmitoyl-carnitine supported ADP-dependent state 3 respiration declined as a result of ischemia. When octanoyl-carnitine was utilized state 3 respiration remained unchanged. State 4 respiration increased during ischemia, an increase that appears specific to fatty acid utilization. Thus, VLCAD represents a likely site for the modulation of substrate utilization during myocardial ischemia. However, the dramatic increase in mitochondrial state 4 respiration would be predicted to accentuate the imbalance between energy production and utilization.
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PMID:Inhibition of very long chain acyl-CoA dehydrogenase during cardiac ischemia. 1585 May 53

To further explore the antiobesity effect of freeze-dried bitter melon (BM) juice, activities of mitochondrial lipid oxidative enzymes as well as the expression of uncoupling proteins and their transcription coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) were determined in diet-induced obese (DIO) rats. Rats were fed high-fat (HF) diets to induce obesity, and the effect of BM was assessed at doses of 0.75, 1.0, or 1.25% (wt:wt). In a dose-response experiment, BM-supplemented rats had lower energy efficiency (g weight gained/kJ consumed), visceral fat mass, serum glucose, and insulin resistance index, but higher plasma norepinephrine than unsupplemented rats (P < 0.05). Hepatic and skeletal muscle triglyceride concentrations were lower in supplemented HF diet-fed rats than in unsupplemented HF diet-fed rats (P < 0.05). An HF diet supplemented with BM elevated activities of hepatic and muscle mitochondrial carnitine palmitoyl transferase-I (CPT-I) and acyl-CoA dehydrogenase (AD) (P < 0.05). In another experiment, BM (1.0 g/100 g) lowered visceral fat mass but increased serum adiponectin concentration in HF diet-fed rats (P < 0.05). In the final study, rats were fed the HF diet with 0, 1.0 or 1.25% BM. Both groups of BM-supplemented rats had higher uncoupling protein 1 in brown adipose tissue (P < 0.05) and uncoupling protein 3 in red gastrocnemius muscle (P < 0.05), measured by Western blotting and RT-PCR, than the controls. The expression of the transcription coactivator PGC-1alpha in both tissues was also significantly elevated in the BM-supplemented rats (P < 0.05). The present results suggest that decreased adiposity in BM-supplemented rats may result from lower metabolic efficiency, a consequence of increased lipid oxidation and mitochondrial uncoupling.
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PMID:Reduced adiposity in bitter melon (Momordica charantia)-fed rats is associated with increased lipid oxidative enzyme activities and uncoupling protein expression. 1625 4

This study examined the effects of different oxygenation levels and substrate availability on cardiac performance, metabolism, and biochemistry in sexually immature male and female rainbow trout (Oncorhynchus mykiss). Ventricle strips were electrically paced (0.5 Hz, 14 degrees C) in hyperoxic or hypoxic Ringer solution. Our results demonstrate that 1) males sustain isometric force production (F) longer than females under hyperoxia (P O2 = 640 mmHg) with exogenous glucose present; 2) contractility is not maintained under moderate (P O2 = 130 mmHg) or severe hypoxia (P O2 = 10-20 mmHg) with glucose in either sex; however, following reoxygenation, F is higher in females compared with males; and 3) female tissue has higher lactate levels, net lactate efflux, and lactate dehydrogenase activity than males, whereas males have higher glycogen, citrate synthase, and beta-hydroxy acyl-CoA dehydrogenase activities, and greater inotropic responses to exogenous glucose and octanoate. No sex differences were detected in responsiveness to epinephrine and inhibitors of glucose transport or activities of hexokinase and pyruvate kinase. We conclude that sex differences exist in rainbow trout cardiac tissue: females appear to prefer glycolysis for ATP production, whereas males have a higher capacity for aerobic and lipid metabolism.
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PMID:Sex differences in energy metabolism and performance of teleost cardiac tissue. 1703 42

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-alpha, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of high-frequency left ventricular pacing (HF + Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. [3H]Oleate and [14C]Glucose were infused intravenously to measure the rate of substrate oxidation. At 21 days of pacing, left ventricular end-diastolic pressure was significantly lower in HF + Feno (14.1 +/- 1.6 mm Hg) compared with HF (18.7 +/- 1.3 mm Hg), but it increased up to 25 +/- 2 mm Hg, indicating end-stage failure, in both groups after 29 +/- 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA beta-oxidation pathway, was reduced in HF versus control (1.46 +/- 0.25 versus 2.42 +/- 0.24 micromol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 +/- 0.18 micromol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.
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PMID:Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure. 1721 46

Central action of leptin on food intake and energy expenditure is integrated with leptin's peripheral action modulating the fatty acid and glucose metabolism and preventing the accumulation of lipids in nonadipose tissues. However, exact mechanism(s) of the leptin's action in the peripheral tissues has not yet been fully elucidated. Therefore, we investigated the effect of a single intravenous injection of leptin on palmitoyl-CoA and palmitoyl-carnitine oxidation rate in liver and skeletal muscle followed by measurements of the carnitine-palmitoyl transferase 1 (CPT1) activity and activities of ss-oxidation enzymes in mitochondria (acyl-CoA dehydrogenase) and in peroxisomes (acyl-CoA oxidase) of rats. Animals were euthanized and tissues and serum harvested 15 min, 1 hour, 3 hours and 6 hours after leptin administration. Intravenous leptin injection increased mitochondrial palmitoyl-CoA oxidation rate in both liver (95%; P<0.025) and skeletal muscle (2.7-fold; P<0.05). This was paralleled by lowering hepatic (-156%; P<0.001) and skeletal muscle (-191%; P<0.001) triglyceride content. Leptin-induced elevation of palmitoyl-CoA oxidation rate in liver was paralleled by increased CPT1 activity (52%; P<0.05) and ss-oxidation capacity (52%; P<0.05). Lack of the leptin's effect on the CPT1-activity in muscle (20%; p=0.09) suggests the existence of an alternative pathway for increasing the palmitoyl-CoA-oxidation rate bypassing the CPT1 regulatory step. Interestingly, leptin stimulated the overall ss-oxidation capacity in muscle by 69% (P=0.027). This may indicate to an involvement of mitochondrial acyl-CoA dehydrogenases as well as of peroxisomal fat catabolism. Taken together, we showed that leptin acutely increases palmitoyl-CoA oxidation rate in liver and in skeletal muscle, which was associated with tissue specific effect on the CPT1 activity as well as on the downstream enzymes of fatty acid oxidation pathways in rat mitochondria and peroxisomes. Tangible evidence for the leptin-induced increase of fatty acid catabolism was provided by a lowered skeletal muscle and hepatic lipid deposition.
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PMID:Concerted action of leptin in regulation of fatty acid oxidation in skeletal muscle and liver. 1747 41


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