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)

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

Generation of reactive oxygen species may contribute to the pathogenesis of diseases involving intracellular lipid accumulation. To explore the mechanisms leading to these pathologies we tested the effects of etomoxir, an inhibitor of carnitine palmitoyltransferase I which contains a fatty acid-derived structure, in C2C12 skeletal muscle cells. Etomoxir treatment for 24 h resulted in a down-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA expression, achieving an 87% reduction at 80 microm etomoxir. The mRNA levels of most of the PPARalpha target genes studied were reduced at 100 microm etomoxir. By using several inhibitors of de novo ceramide synthesis and C(2)-ceramide we showed that they were not involved in the effects of etomoxir. Interestingly, the addition of triacsin C, a potent inhibitor of acyl-CoA synthetase, to etomoxir-treated C2C12 skeletal muscle cells did not prevent the down-regulation in PPARalpha mRNA levels, suggesting that the active form of the drug, etomoxir-CoA, was not involved. Given that saturated fatty acids may generate reactive oxygen species (ROS), we determined whether the addition of etomoxir resulted in ROS generation. Etomoxir increased ROS production and the activity of the well known redox transcription factor NF-kappaB. In the presence of the pyrrolidine dithiocarbamate, a potent antioxidant and inhibitor of NF-kappaB activity, etomoxir did not down-regulate PPARalpha mRNA in C2C12 skeletal muscle cells. These results indicate that ROS generation and NF-kappaB activation are responsible for the down-regulation of PPARalpha and may provide a new mechanism by which intracellular lipid accumulation occurs in skeletal muscle cells.
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PMID:Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in C2C12 skeletal muscle cells. 1179 99

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.
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PMID:Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression. 1214 46

The purpose of this study was to investigate the effects of altering relative intakes of fat and carbohydrates on serum lipid profiles, hepatic acyl-CoA synthetase (ACS), carnitine palmitoyltransferase-I (CPT-I), and the acetyl-CoA carboxlyase (ACC) mRNA level in Sprague-Dawley rats. For four weeks the rats were fed either an AIN-76 diet or one of its modified diets that were supplemented with 20% beef tallow (high-fat diet, HF) and 66.3% sucrose (high-sucrose diet, HS). The HS group had significantly higher serum triglyceride and total cholesterol concentrations when compared with the other groups. Serum LDL-cholesterol concentrations in the HS and HF groups were significantly higher when compared to the normal diet (ND) group. Serum HDL-cholesterol levels of the ND and HS groups were significantly higher than those of the HF group. The hepatic total lipid level of the HF group was significantly higher than those of other groups; triglyceride levels of the HS and HF groups were significantly higher than those of the ND group. Hepatic ACS mRNA levels of the HF group were significantly higher than those of the ND group. Hepatic CPT-I mRNA levels were higher in the HF group than other groups. Also, ACC mRNA levels in the liver increased in the HF group. In conclusion, changes in the composition of dietary fat and carbohydrates could affect the hepatic ACS, CPT-I, and ACC mRNA levels. These results facilitate our understanding of the coordinated regulation of the ACS, CPT-I, and ACC mRNA levels and will serve to enhance our understanding of the molecular mechanisms that underlie the regulation of fatty acid metabolism.
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PMID:The effects of a high-fat or high-sucrose diet on serum lipid profiles, hepatic acyl-CoA synthetase, carnitine palmitoyltransferase-I, and the acetyl-CoA carboxylase mRNA levels in rats. 1278 88

Mitochondrial acylcarnitine synthesis is an obligatory step in the transport of cytosolic long-chain FA into the mitochondria. It is an important control point in the partitioning of cytosolic fatty acids to synthetic pathways or to mitochondrial beta-oxidation. Mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) is the enzyme that catalyzes the transformation of long-chain fatty acylCoA esters to acylcarnitine. Additionally, the isoform of acylCoA synthetase (EC 6.2.1.3) found in mitochondria, which is in close proximity to CPT I on the outer membrane, may act in concert with CPT I to form acylcarnitines from cytosolic nonesterified FA (NEFA). The mitochondrial acylcarnitine synthesis pathway is exposed to multiple fatty acid substrates present simultaneously in the cell milieu, with each fatty acid present at varying pool sizes. The selectivity of this pathway for any particular fatty acid substrate under conditions of multisubstrate availability has not yet been tested experimentally. Our objective was to develop mathematical equations that make use of kinetic constants derived from single-substrate experiments to predict the selectivity of the acylcarnitine synthesis pathway under conditions in which two or more substrates are present simultaneously. In addition, the derived equations must be verifiable by experiment. Our approach was to begin with a Michaelis-Menten model that describes the initial rates of an enzyme system acting on multiple and mutually competitive substrates. From this, we derived equations expressing ratios of reaction rates and fractional turnover rates for pairs of substrates. The derived equations do not require assumptions concerning the degree of enzyme saturation. Using rat mitochondrial preparations and the NEFA substrate pairs, linolenic-oleic acids and palmitic-linoleic acids, we showed that the shape of the experimentally derived data on acylcarnitine synthesis fits the predictions of the derived model equations. We further validated the derived equations by showing that their predictions calculated from previously published kinetic constants were consistent with data from actual experiments. Thus, we are able to conclude that with respect to acylcarnitine synthesis, the fractional turnover rate of the linolenic acid pool would always be 2.9-fold faster than that of the oleate pool regardless of the pool size of either fatty acid. Similarly, the fractional turnover rate of the palmitate pool would always be 1.8-fold faster than that of the linoleate pool regardless of pool size. We extended our kinetic model to more than two mutually competitive substrates. Using previously published rate constants for eight physiologically relevant fatty acids, the derived model predicts that regardless of pool size of any of the fatty acids, the linolenate pool, whether as NEFA or as a CoA ester, would always have the highest fractional turnover rate with respect to acylcarnitine synthesis. Conversely, the stearate pool whether as NEFA or as CoA ester will have the lowest fractional turnover rate relative to all the other fatty acids.
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PMID:Kinetic analysis of the selectivity of acylcarnitine synthesis in rat mitochondria. 1284 98

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
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PMID:Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. 1470 65

The identification of post-translational modifications is difficult especially for hydrophobic membrane proteins. Here we present the identification of several types of protein modifications on membrane proteins isolated from mitochondrial outer membranes. We show, in vivo, that the mature rat liver mitochondrial carnitine palmitoyltransferase-I enzyme is N-terminally acetylated, phosphorylated on two threonine residues, and nitrated on two tyrosine residues. We show that long chain acyl-CoA synthetase 1 is acetylated at both the N-terminal end and at a lysine residue and tyrosine residues are found to be phosphorylated and nitrated. For the three voltage-dependent anion channel isoforms present in the mitochondria, the N-terminal regions of the protein were determined and sites of phosphorylation were identified. These novel findings raise questions about regulatory aspects of carnitine palmitoyltransferase-I, long chain acyl-CoA synthetase and voltage dependent anion channel and further studies should advance our understanding about regulation of mitochondrial fatty acid oxidation in general and these three proteins in specific.
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PMID:Post-translational modifications of rat liver mitochondrial outer membrane proteins identified by mass spectrometry. 1747 30

The purpose of this study was to investigate variations in hepatic regulation of metabolism during the dry period, after parturition, and in early lactation in dairy cows. For this evaluation, cows were divided into 2 groups based on the plasma concentration of beta-hydroxybutyric acid (BHBA) in wk 4 postpartum (PP; group HB, BHBA >0.75 mmol/L; group LB, BHBA <0.75 mmol/L, respectively). Liver biopsies were obtained from 28 cows at drying off (mean 59 +/- 8 d antepartum), on d 1, and in wk 4 and 14 PP. Blood samples were collected every 2 wk during this entire period. Liver samples were analyzed for mRNA abundance of genes related to carbohydrate metabolism (pyruvate carboxylase, PC; phosphoenolpyruvate carboxykinase, PEPCK; citrate synthase, CS), fatty acid biosynthesis (ATP citrate lyase, ACLY) and oxidation (acyl-CoA synthetase long-chain, ACSL; carnitine palmitoyltransferase 1A, CPT 1A; carnitine palmitoyltransferase 2, CPT 2; acyl-coenzyme A dehydrogenase very long chain, ACADVL), cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, HMGCS1), ketogenesis (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2, HMGCS2), and of genes encoding the transcription factors peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferator-activated receptor gamma (PPARgamma), and sterol regulatory element binding factor 1 (SREBF1). Blood plasma was assayed for concentrations of glucose, BHBA, nonesterified fatty acids, cholesterol, triglycerides, insulin, insulin-like growth factor-I, and thyroid hormones. In both groups, plasma parameters followed a pattern usually observed in dairy cows. However, changes were moderate and the energy balance in cows turned positive in wk 7 PP for both groups. Additionally, the energy balance and milk yield were similar for both groups after parturition onwards. Significant group effects were found at drying off, when plasma concentrations of triglycerides were higher in LB than in HB, and in wk 4 PP, when plasma concentrations of glucose and IGF-I were lower in HB than in LB. Similarly, moderate changes in mRNA expression of hepatic genes between the different time points were observed, although HB cows showed more adaptive performance than LB cows based on changes in mRNA expression of PEPCKc, PEPCKm, CS, CPT 1A, CPT 2, and PPARalpha. Part of the variation measured in this study was explained by parity. Significant Spearman rank correlation coefficients between the variables were not similar at each time point and were not similar between the groups at each time point, suggesting that metabolic regulation differs between cows. In conclusion, metabolic regulation in dairy cows is a dynamic system, and differs obviously between cows at different metabolic stages related to parturition.
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PMID:Variation in hepatic regulation of metabolism during the dry period and in early lactation in dairy cows. 1938 50

Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPARalpha and beta/delta, RXRalpha, beta, and gamma, thyroid hormone receptor alpha and beta, and estrogen related receptor alpha (ERRalpha) and their coactivators PGC-1alpha, PGC-1beta, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPARalpha deficient mice, baseline CPT-1beta and FATP-1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPARalpha signaling pathway plays an important role in inducing some of these changes. The decrease in FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.
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PMID:Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm. 1944 62

CPT (carnitine palmitoyltransferase) 1 and CPT2 regulate fatty acid oxidation. Recombinant rat CPT2 was isolated from the soluble fractions of bacterial extracts and expressed in Escherichia coli. The acyl-CoA chain-length-specificity of the recombinant CPT2 was identical with that of the purified enzyme from rat liver mitochondrial inner membranes. The Km for carnitine for both the mitochondrial preparation and the recombinant enzyme was identical. In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold. It decreased the Ki for malonyl-CoA inhibition 60-fold, but had no effect on the apparent Km for myristoyl-CoA. Cardiolipin also activated recombinant CPT2 almost 4-fold, whereas phosphatidylglycerol, phosphatidylserine and phosphatidylcholine activated the enzyme 3-, 2- and 2-fold respectively. Most of the recombinant CPT2 was found to have substantial interaction with cardiolipin. A model is proposed whereby cardiolipin may hold the fatty-acid-oxidizing enzymes in the active functional conformation between the mitochondrial inner and outer membranes in conjunction with the translocase and the acyl-CoA synthetase, thus combining all four enzymes into a functional unit.
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PMID:Membrane microenvironment regulation of carnitine palmitoyltranferases I and II. 2159 56


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