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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Oxidation of long-chain fatty acids increases many-fold in atherosclerotic aortas; this may be due to an increase in the activity of the mitochondrial enzyme hexadecanoyl-CoA: carnitine O-hexadecanoyltransferase EC 2.3.1.23 (trivial name: carnitine palmitoyltransferase, CPT). To investigate this possibility, an assay for arterial CPT was developed and used to measure CPT activity in mitochondrial fractions isolated from aortas of rabbits fed high-fat (HF) or high-fat plus cholesterol (HFC) supplemented diets. The arterial CPT assay was linear with respect to mitochondrial protein between 0.03 and 0.30 mg and assay time between 3 and 12 min. Maximum CPT activity was observed at concentrations of palmitoyl-CoA between 5 and 25 micron, higher concentrations of palmitoyl-CoA inhibited CPT activity. CPT activity was measured in mitochondrial fractions isolated from aortas of rabbits fed the HFC-supplemented diet for up to 48 days. No visible lesions were observed in aortas of rabbits fed HFC-diet for 3,9, or 21 days, however, by 48 days atheromatous lesions covered in excess of 60% of the intimal surface of the aorta. No lesions were visually observed in aortas of rabbits receiving the HF-diet. Despite the development of gross atherosclerotic lesions, there were no changes in CPT activity observed that could account for a dramatic increase in fatty acid oxidation. It is concluded that the increase in beta-oxidation of long-chain fatty acids in atherosclerosis is not attributable to an increase in CPT activity.
Atherosclerosis 1979 Sep
PMID:Carnitine palmitoyltransferase activity in mitochondrial fractions isolated from aortas of rabbits fed cholesterol-supplemented diets. 49 40

The activity of cholinephosphotransferase (EC 2.7.8.2, CPT) which catalyses de novo synthesis of phosphatidylcholine (PC) was studied in aortas of rabbits and rats, and in brain microvessels of rabbits with a cholesterol feeding-induced hypercholesterolemia. Cholesterol feeding produced a marked atheromatous change in rabbit aortas but not in rat aortas. The aortas of cholesterol-fed rabbits displayed a significantly higher CPT activity than the controls. On the other hand, the aortic CPT activity of cholesterol-fed rats was not different from that of control rats. The brain microvessels of cholesterol-fed rabbits having atheromatous aortic lesions did not show any lipid deposition, and CPT activity was similar to that of control rabbits. A tocopherol-deficient, high-cholesterol diet produced microscopical lipid deposits in rat aortas, and CPT activity of these aortas was significantly higher than that of aortas of rats on tocopherol-supplemented diets containing either a normal or high amount of cholesterol. The increase in CPT activity in atheromatous lesion might be closely related to lipid deposition in vessel walls and may be a cause of the increase in PC content in these lesions. Further studies are required to clarify the mechanism of activation of CPT activity in atheromatous conditions.
Atherosclerosis 1988 Dec
PMID:Effect of hypercholesterolemia on cholinephosphotransferase activity in rabbit and rat vessel walls. 285 37

Cardiac ischemia is associated with an impairment in long-chain fatty acid metabolism. We studied carnitine palmitoyltransferase (CPT) in left ventricular biopsies of 6 transplant recipients with ischemia due to atherosclerosis, 4 patients with dilated cardiomyopathy, and 5 donor hearts. Total CPT activity was not significantly different between the three groups (7.9 +/- 3; 6.7 +/- 2, and 8 +/- 3 nmol/min/mg noncollagenous protein). Residual CPT activity after inhibition by malonyl-CoA (0.4 mM) was 38 +/- 11, 36 +/- 5 and 38 +/- 7%. There were no difference in IC50 values. Residual CPT activity after the addition of the detergent Triton X-100 (0.5%) was 58 +/- 17, 54 +/- 2 and 50 +/- 8% (nonsignificant). Our results suggest that (i) total CPT activity and (ii) the sensitivity of the interaction of CPT I with its regulator malonyl-CoA are not affected by cardiac ischemia, and (iii) the ratio of CPT I to CPT II is not altered in cardiac ischemia.
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PMID:Carnitine palmitoyltransferase in patients with cardiac ischemia due to atherosclerotic coronary artery disease and in patients with idiopathic dilated cardiomyopathy. 912 47

The percentage of slow-twitch (ST) fibers in a person's skeletal muscle, e.g. muscle fiber composition (ST-%), may have a significant impact on physical activity, fitness level, serum high density lipoprotein cholesterol (HDL-C) concentration, and ultimately, on the risk of coronary heart disease (CHD). We studied the effect of a 12 month home-based exercise training program on skeletal muscle metabolic activity, serum lipids, and hormones in 12 healthy middle-aged men (sedentary men) with a low level of fitness and leisure-time physical activity (LTPA). Their parameters and changes in them were compared with 12 men of the same age with defined CHD and with two groups (15 each) of physically active men, who had either a high ST-% (high-ST-men) or a low ST-% (low-ST-men). In the sedentary men, CHD-patients and low-ST-men, the mean ST-% (42, 44, and 49%, respectively) was similar but was significantly higher in the high-ST-men (73%). The sedentary men whose LTPA mean was 34 and 19% of the mean of low-ST-men (mean of 2137 kcal/week) and high-ST-men (mean of 3845 kcal/week), respectively, increased their LTPA from a mean of 728-1526 kcal/week (P < 0.01). After training, we found an increase in serum HDL-C by 21%, (P < 0.01) and apo A-I by 36% (P < 0.01), and a decrease in serum LDL-C by 8%. The cholesterol/HDL-C ratio decreased by 17(% (P < 0.01) and the LDL-C/HDL-C ratio decreased by 22% (P < 0.01). Skeletal muscle lipoprotein lipase (LPL) activity increased by 65% (P < 0.001). Moreover, the increase in LPL as well as in HDL-C concentration tended to be more pronounced the higher the level was before training. The oxidative enzyme activity of alpha-ketoglutarate dehydrogenase (KGDH) in skeletal muscle and the activity of carnitine palmitoyltransferase (CPT) in lipid metabolism increased, whereas glycolytic phosphofructokinase (PFK) did not change but the PFK to CPT ratio decreased, which was reflected as a decrease of lactate accumulation during exercise. Increase in CPT activity correlated significantly (r(s) = 0.81, P < 0.01) with the increase in HDL-C concentration. In all men (n = 54), the CPT activity correlated negatively with serum triglyceride concentration (r(s) = -0.34, P < 0.05) but positively with serum HDL-C concentration and ST-% (r(s) = 0.34, P < 0.05 and r(s) = 0.47, P < 0.01, respectively). In all healthy men, (n = 42) LTPA correlated with both Vo2max, and ST-% (r(s) = 0.76, P < 0.001 and r(s) = 0.54, P < 0.001, respectively) and with serum HDL-C and apo A-I concentrations (r(s) = 0.35, P < 0.05 and r(s) = 0.54, P < 0.001, respectively). Serum sex hormones did not show significant associations with serum lipids, but in sedentary men, serum total and free testosterone as well as the ratio of free testosterone to free estradiol decreased significantly after training. These findings confirm the pronounced effects of a home-based exercise training program on CHD risk factors and they underline the importance of considering skeletal muscle properties when studying serum lipids and lipoproteins and their modifications in the field of health-related fitness and physical activity.
Atherosclerosis 1999 Feb
PMID:Significance of skeletal muscle properties on fitness, long-term physical training and serum lipids. 1003 Mar 88

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.
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PMID:Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. 1043 61

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
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PMID:Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. 1134 29

Peroxisome proliferator-activated receptors (PPAR), especially the PPARalpha and PPARgamma, are associated with an extraordinary diverse spectrum of cardiovascular diseases including hypertension, angiogenesis, cardiac hypertrophy, and atherosclerosis. PGAR (for PPAR gamma angiopoietin-related gene) is a recently identified PPAR target gene which is associated with adipose differentiation, systemic lipid metabolism, energy homeostasis, and possibly angiogenesis. We report here that WY-14643, a selective PPARalpha ligand up-regulated PGAR expression in neonatal rat cardiomyocytes. In parallel to activating the expression of vascular endothelial growth factor and glucose transporter-4, hypoxia increased PGAR mRNA levels. PGAR expression was also increased by desferrioxamine and CoCl(2), but not by sodium cyanide, results consistent with the pharmacological features of hypoxia-responsive genes. These studies are the first to demonstrate that hypoxia increases the mRNA levels of a PPAR target gene in cardiomyocytes. Furthermore, infection with adenoviral vectors encoding the wild-type or a hybrid form of HIF-1alpha highly increased PGAR mRNA levels. In contrast, neither hypoxia nor overexpression of HIF-1alpha affected the mRNA levels of PPARalpha, PPAR gamma, and muscle carnitine palmitoyltransferase, a known PPARalpha target gene. These results suggest that hypoxic activation of PGAR expression is likely mediated by HIF-1 but not the PPARalpha/RXR pathway.
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PMID:Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha. 1209 11

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARalpha is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPARalpha activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARalpha activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARalpha activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARalpha activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARalpha activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARalpha activation blocked CE formation induced by TNF-alpha, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-alpha. In conclusion, our results identify a role for PPARalpha in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.
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PMID:Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages. 1257 49

The staggerer mice carry a deletion in the RORalpha gene and have a prolonged humoral response, overproduce inflammatory cytokines, and are immunodeficient. Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-alpha-lipoproteinemia and atherosclerosis. However, relatively little is known about RORalpha in the context of target tissues, target genes, and lipid homeostasis. For example, RORalpha is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure. This lean tissue is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. In particular, the role of RORalpha in skeletal muscle metabolism has not been investigated, and the contribution of skeletal muscle to the ROR-/- phenotype has not been resolved. We utilize ectopic dominant negative RORalpha expression in skeletal muscle cells to understand the regulatory role of RORs in this major mass peripheral tissue. Exogenous dominant negative RORalpha expression in skeletal muscle cells represses the endogenous levels of RORalpha and -gamma mRNAs and ROR-dependent gene expression. Moreover, we observed attenuated expression of many genes involved in lipid homeostasis. Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. In conclusion, we speculate that ROR agonists would increase fatty acid catabolism in muscle and suggest selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis.
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PMID:RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. 1519 55

Increased leptin levels are associated with cardiovascular disease in obesity although the mechanism is unknown. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of macrophage lipid metabolism and its activation by thiazolidinediones protects against atherosclerosis. The aim of this study was to assess the effects of human recombinant leptin on PPARgamma mRNA levels in primary human macrophages and macrophage-derived foam cells. Leptin treatment (100 ng/ml) for 24 h caused a 41% reduction (p < 0.01) in PPARgamma transcript levels in human-derived macrophages. This fall was accompanied by a reduction in the mRNA expression of carnitine palmitoyltransferase (CPT-I) (36%, p < 0.05) and ABCA1 (62%, p < 0.05), whereas CD36 mRNA reduction (34%) was not significant. In macrophage-derived foam cells, leptin at 20 ng/ml reduced PPARgamma mRNA levels by 33% (p < 0.01) and CPT-I by 27% (p < 0.05). At this concentration, leptin did not modify the expression of either ABCA1 or CD36. In agreement with these results, intracellular cholesterol ester accumulation was not altered in macrophage-derived foam cells by leptin at 20 ng/ml. We propose that the reduction in PPARgamma expression in both macrophages and foam cells may be one of the factors linking high leptin levels and cardiovascular disease.
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PMID:Leptin down-regulates peroxisome proliferator-activated receptor gamma (PPAR-gamma) mRNA levels in primary human monocyte-derived macrophages. 1633 97


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