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)

Fish easily accumulate n-3 PUFA of exogenous origin, but the underlying mechanisms are not well established in the whole animal. This study was undertaken to investigate whether this feature was physiologically associated with mitochondrial and peroxisomal capacities that differentially affect FA oxidation. For this purpose, peroxisomal FA oxidation was increased by treating rainbow trout with fenofibrate, which strongly stimulates the peroxisome proliferator-activated receptor-a in rodents. Diets containing EPA and DHA, with or without fenofibrate added, were administered to male trout for 12 d. After treatment, neither liver hypertrophy nor accumulation of fat was apparent within the liver and muscle cells. However, fenofibrate treatment decreased the contents of EPA and DHA in the liver, white muscle, and intraperitoneal fat tissue, which represented (per whole body) at least 280 mg less than in controls. Carnitine-dependent palmitate oxidation rates, expressed per gram of liver, were slightly increased by fenofibrate when measured from tissue homogenates and were unchanged when calculated from isolated mitochondria, relative to control fish. The treatment altered neither carnitine palmitoyltransferase I activity rates, expressed per gram of liver, nor the sensitivity of the enzyme to malonyl-CoA inhibition, but did increase the malonyl-CoA content (+45%). Meanwhile, fenofibrate increased (by about 30%) the peroxisome-related activities, i.e., catalase, carnitine-independent palmitate oxidation, acyl-CoA oxidase, and the peroxisomal FA-oxidizing system, relative to the control group. The data strongly suggest that the induction of peroxisomal activities, some of which being able to oxidize very long chain FA, was responsible for the lower contents of EPA and DHA in the body lipids of fenofibrate-treated trout.
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PMID:Alteration of 20:5n-3 and 22:6n-3 fat contents and liver peroxisomal activities in fenofibrate-treated rainbow trout. 1566 60

This study evaluated the effects of supplementation of carnitine and antioxidants on lipids, carnitine concentrations, and exercise endurance time in both trained and untrained rats as compared to non-supplemented rats. Thirty-two male SD rats, age 7 wk were divided into four groups according to exercise training and modified AIN-76 diets: NTNS (non-trained non-supplemented), NTS (non-trained supplemented), LTNS (long-trained non-supplemented) and LTS (long-trained supplemented). The trained rats were run on a treadmill for 60 min per day (10(0) incline, 20 m/min for 8 wk). Carnitine (0.5%/diet) and vitamin E (0.5 mg/g b.w.) were supplemented in rat diets and vitamin C (0.5 mg/g b.w.) and melatonin (1 microg/g b.w.) were administered into the stomachs of the rats. LTNS and LTS rats had significantly lower serum total lipid, triglyceride, total cholesterol and liver triglycerides, but had higher serum HDL-cholesterol. There were no changes in exercise endurance time by supplementation in untrained animals, however endurance times were longer in LTS animals than in LTNS. The supplementation and training tended to increase carnitine palmitoyltransferase (CPT-I) activities, although the differences were not statistically significant. Likewise, CPT-I mRNA levels were higher in both supplemented and exercise trained rats. These results suggest that supplementation of carnitine and antioxidants may improve lipid profiles and exercise ability in exercise-trained rats.
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PMID:Exercise training and supplementation with carnitine and antioxidants increases carnitine stores, triglyceride utilization, and endurance in exercising rats. 1575 94

The ontogeny of carnitine palmitoyltransferase (CPT) was examined in liver and muscle throughout growth and development of the domestic felid. Homogenates from animals in six age categories (newborn, 24-h, 3-, 6- and 9-week-old, and adult) were examined. Hepatic CPT specific activity increased progressively from birth to 6 weeks and then declined slightly into adulthood, with maximal values for animals greater than 24 h of age [171 nmol/(min g wet tissue)] being 70% higher than for newborns [99 nmol/(min g wet tissue)] (P<.05). Specific activity in adults was similar to that in 6- and 9-week-old juveniles. Total hepatic CPT activity [nmol/(min liver)] increased linearly with age, but the activity expressed per kg body weight [nmol/(min kg BW)] declined after 3 weeks. In contrast, skeletal muscle CPT-specific activity remained unchanged from birth to 3 weeks and then increased significantly, with maximal values at 9 weeks being 90% greater than those for young animals (newborn to 3 weeks; P<.05), whereas specific activity in adults was 50% lower than that observed in 9-week-old animals (P<.05). Hepatic and muscle apparent Km's for carnitine averaged 440 microM and did not vary with age. Hepatic carnitine concentrations remained relatively constant during development, but were lower in adult lactating females, whereas skeletal muscle concentrations increased markedly with age. Hepatic concentrations were 20-50% higher than apparent Km's for carnitine in young and growing animals, but concentrations were similar to the apparent Km at 6 weeks and significantly lower than the apparent Km in adults. Carnitine concentrations in skeletal muscle were 37% lower than apparent Km during the neonatal period, but significantly higher in cats >3 weeks of age. We conclude that postnatal increases in CPT activity support increased capacity for fatty acid oxidation in the developing felid and that dietary carnitine may be required to maximize enzyme activity.
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PMID:Ontogeny and kinetics of carnitine palmitoyltransferase in liver and skeletal muscle of the domestic felid (Felis domestica). 1593 44

Carnitine palmitoyltransferases 1 and 2 (CPTs) facilitate the import of long-chain fatty acids into mitochondria. Modulation of the catalytic activity of the CPT system is currently under investigation for the development of novel drugs against diabetes mellitus. We report here the 1.6 A resolution structure of the full-length mitochondrial membrane protein CPT-2. The structure of CPT-2 in complex with the generic CPT inhibitor ST1326 ([R]-N-[tetradecylcarbamoyl]-aminocarnitine), a substrate analog mimicking palmitoylcarnitine and currently in clinical trials for diabetes mellitus treatment, was solved at 2.5 A resolution. These structures of CPT-2 provide insight into the function of residues involved in substrate binding and determination of substrate specificity, thereby facilitating the rational design of antidiabetic drugs. We identify a sequence insertion found in CPT-2 that mediates membrane localization. Mapping of mutations described for CPT-2 deficiency, a hereditary disorder of lipid metabolism, implies effects on substrate recognition and structural integrity of CPT-2.
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PMID:The crystal structure of carnitine palmitoyltransferase 2 and implications for diabetes treatment. 1661 1

Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and CoA. The members of the family can be classified on the basis of their acyl-CoA selectivity. Carnitine acetyltransferases (CrATs) are very active toward short-chain acyl-CoAs but not toward medium- or long-chain acyl-CoAs. Previously, we identified an amino acid residue (Met(564) in rat CrAT) that was critical to fatty acyl-chain-length specificity. M564G-mutated CrAT behaved as if its natural substrates were medium-chain acyl-CoAs, similar to that of carnitine octanoyltransferase (COT). To extend the specificity of rat CrAT to other substrates, we have performed new mutations. Using in silico molecular modeling procedures, we have now identified a second putative amino acid involved in acyl-CoA specificity (Asp(356) in rat CrAT). The double CrAT mutant D356A/M564G showed 6-fold higher activity toward palmitoyl-CoA than that of the single CrAT mutant M564G and a new activity toward stearoyl-CoA. We show that by performing two amino acid replacements a CrAT can be converted into a pseudo carnitine palmitoyltransferase (CPT) in terms of substrate specificity. To change CrAT specificity from carnitine to choline, we also prepared a mutant CrAT that incorporates four amino acid substitutions (A106M/T465V/T467N/R518N). The quadruple mutant shifted the catalytic discrimination between l-carnitine and choline in favor of the latter substrate and showed a 9-fold increase in catalytic efficiency toward choline compared with that of the wild-type. Molecular in silico docking supports kinetic data for the positioning of substrates in the catalytic site of CrAT mutants.
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PMID:Mutagenesis of specific amino acids converts carnitine acetyltransferase into carnitine palmitoyltransferase. 1668 86

The overall objective is to test the hypothesis that conjugated linoleic acid (CLA) has beneficial effects in Atlantic salmon as a result of affecting lipid and FA metabolism. The specific aims of the present study were to determine the effects of CLA on some key pathways of FA metabolism, including FA oxidation and highly unsaturated FA (HUFA) synthesis. Salmon smolts were fed diets containing two levels of fish oil (low, approximately 17%, and high, approximately 34%) containing three levels of CLA (a 1:1 mixture of cis-9,trans-11 and trans-10,cis-12 at 0, 1, and 2% of diet) for 3 mon. The effects of dietary CLA on HUFA synthesis and beta-oxidation were measured, and the expression of key genes in the FA oxidation and HUFA synthesis pathways, and the potentially important transcription factors peroxisome proliferators activated receptors (PPAR), were determined in selected tissues. Liver HUFA synthesis and desaturase gene expression was increased by dietary CLA and decreased by high dietary oil content. Carnitine palmitoyltransferase-I (CPT-I) activity and gene expression were generally increased by CLA in muscle tissues although they were relatively unaffected by dietary oil content. In general CPT-I activity or gene expression was not correlated with P-oxidation. Dietary CLA tended to increase PPARalpha and beta gene expression in both liver and muscle tissues, and PPARgamma in liver. In summary, gene expression and activity of the FA pathways were altered in response to dietary CLA and/or oil content, with data suggesting that PPAR are also regulated in response to CLA. Correlations were observed between dietary CLA, liver HUFA synthesis and desaturase gene expression, and liver PPARalpha expression, and also between dietary CLA, CPT-I expression and activity, and PPARalpha expression in muscle tissues. In conclusion, this study suggests that dietary CLA has effects on FA metabolism in Atlantic salmon and on PPAR transcription factors. However, further work is required to assess the potential of CLA as a dietary supplement, and the role of PPAR in the regulation of lipid metabolism in fish.
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PMID:Influence of dietary oil content and conjugated linoleic acid (CLA) on lipid metabolism enzyme activities and gene expression in tissues of Atlantic salmon (Salmo salar L.). 1693 87

Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial beta-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5-11.5. Also, while there were normal percentages of CPT-1b+/- pups born from both male and female CPT-1b+/- mice crossed with wild-type mates, the number of CPT-1b+/- pups from CPT-1b+/- breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated approximately 50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/- male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/- mice had approximately 60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/- mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, approximately 7% CPT-1b+/- mice (n=30) developed fatal hypothermia following a 3h cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6h), significantly more CPT-1b+/- mice developed fatal hypothermia (52% CPT-1b+/- mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/- mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.
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PMID:Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse. 1802 82

Carnitine palmitoyltransferase-II (CPT-II) deficiency is an autosomal recessive disease involving mitochondrial long-chain fatty acid oxidation that results in a distinct clinical phenotype. Reported herein is an autopsy case of the neonatal form of CPT-II deficiency in a 2-day-old Japanese boy who died due to a severe hepatocardiomuscular disease with an extremely early onset. Autopsy examination indicated massive pulmonary atelectasis with intra-alveolar hemorrhage, and the patient had marked cardiomegaly and hepatomegaly, both of which demonstrated the presence of abundant intracytoplasmic steatosis. Three years after the autopsy examination, CPT-II deficiency was suggested by acylcarnitine analysis of dried-blood on filter paper from the patient's younger sister at the age of 1. The younger sister also died due to sudden onset of cardiopulmonary arrest; a remarkable increase of long-chain (C16-18) acylcarnitines was detected on tandem mass spectrometry (TMS). Decreased CPT-II expression was detected in the liver, heart and kidney of the patient. Furthermore, del1737C, a novel mutation of the CPT-II gene, was detected as well as a known GA transition at codon 174. Eventually, laboratory and autopsy findings led to diagnosis of the neonatal form of CPT-II deficiency. TMS can be expected to be widely used to detect metabolic disorders in neonates.
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PMID:Autopsy case of the neonatal form of carnitine palmitoyltransferase-II deficiency triggered by a novel disease-causing mutation del1737C. 1857 13

Effects of increasing maternal L-carnitine on carnitine status and energy metabolism in the fetus were evaluated by feeding pregnant swine a corn-soybean-based diet containing either 0 or 50 mg/kg added L-carnitine (n = 10/treatment) during the first 70 d of gestation. Carnitine, carnitine palmitoyltransferase (CPT), and pyruvate dehydrogenase complex (PDHC) activities were analyzed in tissues collected from fetuses on d 55 and 70. Maternal L-carnitine supplementation increased both fetal free and long-chain carnitine concentrations by 45% in liver and free carnitine by 31% in heart tissues but did not affect kidney tissue. Elevations in free and acylcarnitines increased with gestational age from 55 to 70 d in liver but not in heart and kidney. The increased carnitine concentrations resulted in a 45% increase in PDHC activity in heart and liver on d 70 of gestation but did not affect kidney and liver on d 55 of gestation. The increases in carnitine concentrations were accompanied by a 70% increase in hepatic CPT activity in 70-d-old fetuses, but activities in heart and kidney were unaffected. The Michaelis constant (K(m)) of CPT for carnitine in fetal tissues was not influenced by carnitine supplementation (P > 0.1). Notably, the concentrations of carnitine measured on d 70 were only 25-40% of the K(m) values in liver, 60-70% in heart, and 30-40% in kidney (P < 0.001). We conclude that carnitine ingestion during pregnancy increases fetal carnitine concentrations and stimulates heart PDHC and liver CPT activity without altering carnitine K(m).
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PMID:Maternal dietary L-carnitine supplementation influences fetal carnitine status and stimulates carnitine palmitoyltransferase and pyruvate dehydrogenase complex activities in swine. 1902 57

Antenatal presentation of carnitine palmitoyltransferase type II deficiency due to mutations in the CPT2 gene has been rarely reported. We report an Ashkenazi Jewish family with 3 terminated pregnancies for multicystic kidneys and/or hydrocephalus. Fetal autopsy after termination of the couple's 4th pregnancy (sib 2) showed renal parenchyma replaced by cysts that appeared to increase in diameter toward the medulla. Fetopsy after termination of the 7th pregnancy (sib 3) revealed micrognathia; hypospadias; cystic renal dysplasia; hepatosteatosis; and lipid accumulation in the renal tubular epithelium, myocardium, and skeletal muscle. Microvascular proliferative changes and focal polymicrogyria were seen in the brain. A beta-oxidative enzyme deficiency was suspected. CPT2 gene analysis showed a homozygous complex haplotype for the F448L mutation associated with a c.del1238_1239AG (p.Q413fs) truncating mutation in exon 4. Carnitine palmitoyltransferase type II deficiency should be included in the differential diagnosis in fetuses of Ashkenazi origin with multicystic kidneys and unusual cerebral findings.
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PMID:Severe infantile carnitine palmitoyltransferase II deficiency in 19-week fetal sibs. 1933 26


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