Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice deficient for either long-chain acyl-CoA dehydrogenase (LCAD-/-) or very-long-chain acyl-CoA dehydrogenase (VLCAD-/-) develop hepatic steatosis upon fasting, due to disrupted mitochondrial fatty acid oxidation. Moreover, neither mouse model can maintain core body temperature when exposed to cold. We investigated the effects of fasting and cold exposure on gene expression in these mice. Non-fasted LCAD-/- mice showed gene expression changes indicative of fatty liver, including elevated mRNA levels for peroxisome proliferator-activated receptor-gamma (PPARgamma) and genes involved in lipogenesis. In LCAD-/- and VLCAD-/- mice challenged with fasting and cold exposure, expression of fatty acid oxidation genes was elevated in liver, consistent with increased PPARalpha activity. This effect was not seen in brown adipose tissue, suggesting that expression of these genes may be regulated differently than in liver. The effect of acute cold exposure on expression of fatty acid oxidation genes was measured in peroxisome proliferator-activated receptor (PPAR)-alpha-deficient mice (PPARalpha-/-) and controls. In PPARalpha-/- mice, basal expression of the acyl-CoA dehydrogenases was reduced in liver but was not altered in brown adipose tissue. While cold altered the expression of PPARgamma, sterol-regulatory element binding protein-1 (SREBP-1), ATP citrate lyase, and the uncoupling proteins in brown adipose tissue from both PPARalpha-/- and control mice, fatty acid oxidation genes were unaffected. Thus, while fatty acid oxidation appears critical for non-shivering thermogenesis, expression of the acyl-CoA dehydrogenases is not influenced by cold exposure. Moreover, mitochondrial fatty acid oxidation genes are not regulated by PPARalpha in brown adipose tissue as they are in liver.
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PMID:Differential induction of genes in liver and brown adipose tissue regulated by peroxisome proliferator-activated receptor-alpha during fasting and cold exposure in acyl-CoA dehydrogenase-deficient mice. 1563 94

Thiazolidenediones such as pioglitazone improve insulin sensitivity in diabetic patients by several mechanisms, including increased uptake and metabolism of free fatty acids in adipose tissue. The purpose of the present study was to determine the effect of pioglitazone on mitochondrial biogenesis and expression of genes involved in fatty acid oxidation in subcutaneous fat. Patients with type 2 diabetes were randomly divided into two groups and treated with placebo or pioglitazone (45 mg/day) for 12 weeks. Mitochondrial DNA copy number and expression of genes involved in mitochondrial biogenesis were quantified by real-time PCR. Pioglitazone treatment significantly increased mitochondrial copy number and expression of factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and mitochondrial transcription factor A. Treatment with pioglitazone stimulated the expression of genes in the fatty acid oxidation pathway, including carnitine palmitoyltransferase-1, malonyl-CoA decarboxylase, and medium-chain acyl-CoA dehydrogenase. The expression of PPAR-alpha, a transcriptional regulator of genes encoding mitochondrial enzymes involved in fatty acid oxidation, was higher after pioglitazone treatment. Finally, the increased mitochondrial copy number and the higher expression of genes involved in fatty acid oxidation in human adipocytes may contribute to the hypolipidemic effects of pioglitazone.
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PMID:Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. 1585 25

Insulin resistance-related obesity and diabetes mellitus are the predominant causes of fatty liver disease. Here we examine the effects of dietary diacylglycerol (DG), which is a minor component of plant oils, on lipid accumulation and the expression of genes involved in lipid metabolism in the liver. The animals were fed diets containing either 10% triacylglycerol (TG), 10% TG + 4% alpha-linolenic acid-rich TG (ALATG) or 10% TG + 4% alpha-linolenic acid-rich diacylglycerol (ALADG) for a period of 1 month. Supplementation with ALADG significantly inhibited hepatic triglyceride accumulation; this was accompanied by the up-regulation of beta-oxidation activity, and acyl-CoA oxidase (ACO) and medium-chain acyl-CoA dehydrogenase (MCAD) mRNA levels. By contrast, no significant changes were observed in the levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and sterol regulatory element-binding protein-1 (SREBP-1) mRNAs. These results indicate that ALADG might be useful in the prevention of fatty liver formation; this effect could be closely related to the stimulation of lipid catabolism in the liver. In addition, our findings suggest that both acylglycerol structure (that is, the structural difference between TG and DG) and fatty-acid species affect the nutritional behaviour of dietary lipids.
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PMID:Supplementation with alpha-linolenic acid-rich diacylglycerol suppresses fatty liver formation accompanied by an up-regulation of beta-oxidation in Zucker fatty rats. 1586 69

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased; however, the mechanisms involved in the pathogenesis of NAFLD have not been thoroughly investigated in humans. In this study, we evaluated the expression of fatty acid metabolism-related genes in NAFLD. Real-time RT-PCR was performed using liver biopsy samples from 12 NAFLD patients. The target genes studied were: acetyl-CoA carboxylase (ACC) 1, ACC2, and fatty acid synthase (FAS) for the evaluation of de novo fatty acid synthesis; carnitine palmitoyltransferase 1a (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), and long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase alpha (HADHalpha) for beta-oxidation in the mitochondria; peroxisome proliferator-activated receptor- (PPAR-) alpha and cytochrome P450 2E1 (CYP2E1) for oxidation in peroxisomes and microsomes (endoplasmic reticulum) respectively; and diacylglycerol O-acyltransferase 1 (DGAT1), PPAR-gamma, and hormone sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, expression of ACC1 and ACC2, but not FAS was increased, indicating that de novo fatty acid synthesis is enhanced in NAFLD. In contrast, expression of CTP1a, a rate-limiting enzyme, was remarkably decreased, indicating that beta-oxidation in the mitochondria was decreased, although the expression of LCAD and HADHalpha was increased. Expression of PPAR-alpha was increased, whereas that of CYP2E1 was reduced. The expression of DGAT1, PPAR-gamma, and HSL was enhanced. These data suggest that in NAFLD, increased de novo synthesis and decreased beta-oxidation in the mitochondria lead to accumulation of fatty acids in hepatocytes, although the extent of oxidation in peroxisomes and microsomes remains unclear.
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PMID:Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. 1614 97

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

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARalpha agonist fenofibrate (150 mg.kg(-1).day(-1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 +/- 6%) compared with sham operated (86 +/- 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.
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PMID:Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure. 1633 30

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.
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PMID:Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin. 1644 71

Aging induces complex changes in myocardium bioenergetic and contractile properties. Using F344BNF(1) rats, we examined age-dependent changes in myocardial bioenergetic enzymes (catalytic activities and transcript levels) and mRNA levels of putative transcriptional regulators of bioenergetic genes. Very old rats (35 months) showed a 22% increase in ventricular mass with no changes in DNA or RNA per gram. Age-dependent cardiac hypertrophy was accompanied by complex changes in mitochondrial enzymes. Enzymes of the Krebs cycle and electron transport system remained within 15% of the values measured in adult heart, significant decreases occurring in citrate synthase (10%) and aconitase (15%). Transcripts for these enzymes were largely unaffected by aging, although mRNA levels of putative transcriptional regulators of the enzymes (nuclear respiratory factor (NRF) 1 and 2 alpha subunit) increased by about 30%-50%. In contrast, enzymes of fatty acid oxidation exhibited a more diverse pattern, with a 50% decrease in beta-hydroxyacyl-CoA dehydrogenase (HOAD) and no change in long-chain acyl-CoA dehydrogenase or carnitine palmitoyltransferase. Transcript levels for fatty acid oxidizing enzymes covaried with HOAD, which declined significantly by 30%. There were no significant changes in the relative transcript levels of regulators of genes for fatty acid oxidizing enzymes: peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARbeta, or PPARgamma coactivator-1alpha (PGC-1alpha). There were no changes in the mRNA levels of Sirt1, a histone-modifying enzyme that interacts with PGC-1alpha. Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation.
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PMID:Control of mitochondrial gene expression in the aging rat myocardium. 1660

Aging is associated with metabolic syndrome, tissue damage by cytotoxic lipids, and altered fatty acid handling. Fat tissue dysfunction may contribute to these processes. This could result, in part, from age-related changes in preadipocytes, since they give rise to new fat cells throughout life. To test this hypothesis, preadipocytes cultured from rats of different ages were exposed to oleic acid, the most abundant fatty acyl moiety in fat tissue and the diet. At fatty acid concentrations at which preadipocytes from young animals remained viable, cells from old animals accumulated lipid in multiple small lipid droplets and died, with increased apoptotic index, caspase activity, BAX, and p53. Rather than inducing apoptosis, oleic acid promoted adipogenesis in preadipocytes from young animals, with appearance of large lipid droplets. CCAAT/enhancer-binding protein-alpha (C/EBPalpha) and peroxisome proliferator-activated receptor-gamma (PPARgamma) increased to a greater extent in cells from young than old animals after oleate exposure. Oleic acid, but not glucose, oxidation was impaired in preadipocytes and fat cells from old animals. Expression of carnitine palmitoyltransferase (CPT)-1, which catalyzes the rate-limiting step in fatty acid beta-oxidation, was not reduced in preadipocytes from old animals. At lower fatty acid levels, constitutively active CPT I expression enhanced beta-oxidation. At higher levels, CPT I was not as effective in enhancing beta-oxidation in preadipocytes from old as young animals, suggesting that mitochondrial dysfunction may contribute. Consistent with this, medium-chain acyl-CoA dehydrogenase expression was reduced in preadipocytes from old animals. Thus preadipocyte fatty acid handling changes with aging, with increased susceptibly to lipotoxicity and impaired fatty acid-induced adipogenesis and beta-oxidation.
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PMID:Aging results in paradoxical susceptibility of fat cell progenitors to lipotoxicity. 1714 51

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


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