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)

Mitochondrial outer membranes were prepared from livers of rats that were in the normal fed state, starved for 48 h, or made diabetic by injection of streptozotocin. Membranes were also prepared from starved late-pregnant rats. The latter three conditions have previously been shown to induce varying degrees of desensitization of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA inhibition. We measured the fluorescence polarization anisotropy of two probes, 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene-p-toluenes ulfonate (TMA-DPH) which, when incorporated into membranes, report on the hydrophobic core and on the peripheral regions of the bilayer, respectively. The corresponding polarization indices (rDPH and rTMA-DPH) were calculated. In membranes of all three conditions characterized by CPT I desensitization to malonyl-CoA, rDPH was decreased, whereas there was no change in rTMA-DPH, indicating that CPT I is sensitive to changes in membrane core, rather than peripheral, lipid order. The major lipid components of the membranes were analyzed. Although significant changes with physiological state were observed, there was no consistent pattern of changes in gross lipid composition accompanying the changes to membrane fluidity and CPT I sensitivity to malonyl-CoA. We conclude that CPT I kinetic characteristics are sensitive to changes in lipid composition that are localized to specific membrane microdomains.
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PMID:Lipid molecular order in liver mitochondrial outer membranes, and sensitivity of carnitine palmitoyltransferase I to malonyl-CoA. 959 Jun 24

We evaluated the activities of carnitine palmitoyltransferase (CPT), carnitine octanoyltransferase (COT), and carnitine acetyltransferase (CAT) in the frontal cortex, temporal cortex, parietal cortex, hippocampus, and cerebellum of Alzheimer disease (AD) patients and normal human brains. There were no significant differences in total CPT activity, its inhibition by malonyl-CoA, the effect of the detergent Triton X-100 on CPT activity, COT activity, and CAT activity in any of the brain regions examined whether activities were expressed as grams of wet weight or corrected for noncollagen protein content. The addition of Triton X-100 increased CAT activity by 50%. Our results suggest that there is no defect of fatty acid transport within the AD brain cell. Total CPT activity, COT activity, and CAT activity are not affected in AD nor is the ratio of CPT I to CPT II altered in the AD versus the normal human brain.
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PMID:Carnitine acyltransferases are not changed in Alzheimer disease. 965 Nov 34

The effects of fatty acids on the induction of apoptosis were studied over a 24 hour period in Hep2 human larynx tumour cells. While oleic and linoleic acids had little effect on the apoptotic index, the polyunsaturated fatty acids alpha-linolenic, gamma-linolenic, arachidonic, eicosapentaenoic and docosahexaenoic acids all induced apoptosis, beginning at approximately 6 hours after fatty acid exposure. By 24 hours after exposure, the apoptotic index had reached as much as 19% in the presence of docosahexaenoic or alpha-linolenic acid. The correlation between degree of unsaturation of the 18-carbon fatty acids and the apoptotic index was r2 = 0.45, 0.89, 0.84 and 0.98 at 6, 8, 12 and 24 hours, respectively. The correlation between mitochondrial carnitine palmitoyltransferase I (CPT I) activity, 6 hours after exposure, and the apoptotic index was r2 = 0.842 and 0.798 at 12 and 24 hours, respectively. The inhibition of CPT I and subsequent fatty acid oxidation by polyunsaturated fatty acids leads to a significant increase in apoptosis, suggesting that CPT I may be involved in the processes of programmed cell death in Hep2 human tumour cells.
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PMID:Induction of apoptosis by polyunsaturated fatty acids and its relationship to fatty acid inhibition of carnitine palmitoyltransferase I activity in Hep2 cells. 967 54

Mitochondrial fatty acid beta-oxidation is important for energy production, which is stressed by the different defects found in this pathway. Most of the enzyme deficiencies causing these defects are well characterized at both the protein and genomic levels. One exception is carnitine palmitoyltransferase I (CPT I) deficiency, of which until now no mutations have been reported although the defect is enzymatically well characterized. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Here we report the first delineation of the molecular basis of hepatic CPT I deficiency in a new case. cDNA analysis revealed that this patient was homozygous for a missense mutation (D454G). The effect of the identified mutation was investigated by heterologous expression in yeast. The expressed mutant CPT IA displayed only 2% of the activity of the expressed wild-type CPT IA, indicating that the D454G mutation is the disease-causing mutation. Furthermore, in patient's fibroblasts the CPT IA protein was markedly reduced on immunoblot, suggesting that the mutation renders the protein unstable.
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PMID:Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. 969 Oct 89

Using a rat model of isocaloric protein restriction (8 v 20% protein diet), the study tested the hypothesis that growth retardation in utero, induced by maternal protein malnutrition, influences cardiac carnitine palmitoyltransferase (CPT) activity and regulation by malonyl-CoA in the newborn period, as well as in the offspring's adult life. The susceptibility of cardiac CPT to inhibition by malonyl-CoA was greater in adulthood than in hearts of 4-day-old neonatal rats, consistent with decreased expression of the L-CPT I isoform and increased expression of the M-CPT I isoform in adulthood. Maternal protein restriction during pregnancy resulted in reduced foetal growth and significantly (P < 0.05) lower rates of cardiac glucose utilization in vivo in the adult offspring, suggesting a switch to the use of substrates other than glucose. Maternal protein restriction did not affect CPT activity in hearts of 4-day-old neonatal offspring and, furthermore, the relative sensitivity of CPT activity to malonyl-CoA inhibition was unchanged by maternal protein restriction. It is therefore unlikely that maternal protein malnutrition has any major impact on cardiac mitochondrial fatty acid oxidation in the offspring during early postnatal development through altered regulatory characteristics of CPT. Transfer of rats previously maintained on 8% protein diet to 20% protein diet at weaning did not influence age-dependent changes in cardiac CPT activity or increase the susceptibility of cardiac CPT to inhibition by malonyl-CoA. Cardiac CPT activities and the susceptibility of cardiac CPT activities to malonyl-CoA inhibition in adulthood did not differ significantly between rats maintained on 8 or 20% protein throughout. Palmitate oxidation was suppressed to a similar extent by glucose in cardiac myocytes from adult rats maintained on 20% protein diet or 8% protein diet throughout and from rats transferred from 8 to 20% protein diet at weaning. The results exclude cardiac CPT activity as a direct target for the metabolic programming of cardiac function and cardiovascular disease associated with early growth retardation.
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PMID:Impact of protein restriction on the regulation of cardiac carnitine palmitoyltransferase by malonyl-CoA. 971 Aug 6

To explore the gene regulatory mechanisms involved in the metabolic control of cardiac fatty acid oxidative flux, the expression of muscle-type carnitine palmitoyltransferase I (M-CPT I) was characterized in primary cardiac myocytes in culture following exposure to the long-chain mono-unsaturated fatty acid, oleate. Oleate induced steady-state levels of M-CPT I mRNA 4.5-fold. The transcription of a plasmid construct containing the human M-CPT I gene promoter region fused to a luciferase gene reporter transfected into cardiac myocytes, was induced over 20-fold by long-chain fatty acid in a concentration-dependent and fatty acyl-chain length-specific manner. The M-CPT I gene promoter fatty acid response element (FARE-1) was localized to a hexameric repeat sequence located between 775 and 763 base pairs upstream of the initiator codon. Cotransfection experiments with expression vectors for the peroxisome proliferator-activated receptor alpha (PPARalpha) demonstrated that FARE-1 is a PPARalpha response element capable of conferring oleate-mediated transcriptional activation to homologous or heterologous promoters. Electrophoretic mobility shift assays demonstrated that PPARalpha bound FARE-1 with the retinoid X receptor alpha. The expression of M-CPT I in hearts of mice null for PPARalpha was approximately 50% lower than levels in wild-type controls. Moreover, a PPARalpha activator did not induce cardiac expression of the M-CPT I gene in the PPARalpha null mice. These results demonstrate that long-chain fatty acids regulate the transcription of a gene encoding a pivotal enzyme in the mitochondrial fatty acid uptake pathway in cardiac myocytes and define a role for PPARalpha in the control of myocardial lipid metabolism.
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PMID:Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. 972 88

The mitochondrial outer membrane enzyme carnitine palmitoyltransferase I (CPT I) plays a major role in the regulation of fatty acid entry into the mitochondrial matrix for beta-oxidation by virtue of its inhibition by malonyl-CoA. Two isoforms of CPT I, the liver type (L) and muscle type (M), have been identified, the latter being 100 times more sensitive to malonyl-CoA and having a much higher Km for the substrate carnitine. Here we have examined the roles of different regions of the CPT I molecules in their response to malonyl-CoA, etomoxir (an irreversible inhibitor) and carnitine. To this end, we analysed the properties of engineered rat CPT I constructs in which (a) the N-terminal domain of L-CPT I was deleted, (b) the N-terminal domains of L- and M-CPT I were switched, or (c) each of three conserved histidine residues located towards the N-terminus in L-CPT I was mutated. Several novel points emerged: (1) whereas the N-terminal domain is critical for a normal malonyl-CoA response, it does not itself account for the widely disparate sensitivities of the liver and muscle enzymes to the inhibitor; (2) His-5 and/or His-140 probably play a direct role in the malonyl-CoA response, but His-133 does not; (3) the truncated, chimaeric and point- mutant variants of the enzyme all bound the covalent, active-site- directed ligand, etomoxir; and (4) only the most radical alteration of L-CPT I, i.e. deletion of the N-terminal 82 residues, affected the response to carnitine. We conclude that the N-terminal domain of CPT I plays an essential, but permissive, role in the inhibition of the enzyme by malonyl-CoA. By contrast, the larger C-terminal region dictates the degree of sensitivity to malonyl-CoA, as well as the response to carnitine; it is also sufficient for etomoxir binding. Additionally, further weight is added to the notion that one or more histidine residues may be involved in the CPT I-malonyl-CoA interaction.
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PMID:Roles of the N- and C-terminal domains of carnitine palmitoyltransferase I isoforms in malonyl-CoA sensitivity of the enzymes: insights from expression of chimaeric proteins and mutation of conserved histidine residues. 979 89

Because we had found whole testis from adult rats to be much richer in the messenger RNA for the muscle (M) than for the liver (L) form of mitochondrial carnitine palmitoyltransferase I (CPT I), we sought to determine which cell type(s) accounts for this expression pattern and how it might relate to reproductive function. Studies with immature (14-day-old) and adult animals included 1) Northern blot analysis of testis mRNA; 2) in situ hybridization with slices of testis; 3) enzyme assays for CPT I, CPT II, and carnitine acetyltransferase (CAT) in testicular germ cells and nongerm cells, together with measurement of the malonyl-coenzyme A (CoA) sensitivity and affinity for carnitine of CPT I; 4) labeling of testicular CPT I with [3H]etomoxir, a covalent inhibitor of the enzyme; and 5) the response of testicular and nontesticular CPT I to dietary etomoxir. The data established the following: 1) L-CPT I was the sole isoform detected in immature testis. 2) Expression of the M-CPT I gene was associated only with meiotic and postmeiotic germ cells. 3) Adult testis contains a mixture of the L- and M-CPT I enzymes, the L and M form dominating in extratubular cells and spermatids, respectively. Mature epididymal spermatozoa appear to be devoid of CPT I activity while possessing abundant levels of CPT II and CAT. 4) Five days of dietary etomoxir treatment at a dose that resulted in essentially complete inhibition of CPT I in liver, heart, skeletal muscle, and kidney was totally without effect on either the L- or M-type enzyme in the testis of mature rats. The data point to an important role for transient expression of M-CPT I, coupled with sustained activity of CAT, in the maturation and/or function of rat sperm. They also suggest that, at least in the case of one CPT I inhibitor (etomoxir), the testis is unusually resistant to the agent when given orally.
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PMID:Expression and possible role of muscle-type carnitine palmitoyltransferase I during sperm development in the rat. 982 84

The five-fold higher carnitine content in the liver of fenofibrate-treated rats addresses the question about the possible role of this enhancement in the hypolipidaemic effect of the drug and the underlying mechanisms. When fenofibrate was administered with mildronate (a gamma-butyrobetaine hydroxylase inhibitor) in suitable amount, the content in carnitine was found to be normalized in liver. However, triglyceride contents of liver and serum were then at least as low as in rats treated by fenofibrate only. When carnitine concentration was lowered by mildronate to the third of the normal value, a marked increase in triglycerides occurred both in liver and serum, while the five-fold increase in carnitine due to fenofibrate enhanced blood ketone body concentration with no effect on liver and serum triglycerides. Data suggest that the normal carnitine concentration is largely sufficient to meet the usual requirement for carnitine palmitoyltransferase I activity (CPT I). In rat liver, increase in mitochondrial CPT I activity and in peroxisomal fatty acid oxidation may constitute part of the hypolipidaemic effect of fenofibrate.
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PMID:Hypolipidaemic effects of fenofibrate are not altered by mildronate-mediated normalization of carnitine concentration in rat liver. 989 54

Liver carnitine palmitoyltransferase I (CPT I), the rate-limiting enzyme of mitochondrial beta-oxidation, rapidly loses its activity when hepatocytes are put in culture. 3-Thia fatty acids reactivate the enzyme and can increase its activity 3-4-fold in 5-10 min. Normal fatty acids are also able to stimulate CPT I, but to a limited extent, compared to 3-thia fatty acid. This activation does not affect malonyl-CoA sensitivity. CPT I in hepatocytes from both fasted and fasted-carbohydrate refed rats is inactivated and reactivated to a similar extent. Free dodecylthioacetic acid (DTA) is at least as efficient as DTA-CoA as activator. CPT I activity in isolated mitochondria is not influenced by incubation with DTA, suggesting that the regulation of CPT I depends on an extramitochondrial component(s) in the cell. It is concluded that fatty acids activate pre-existing, inactive CPT I without involvement of gene transcription and independently of malonyl-CoA.
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PMID:Short-term regulation of carnitine palmitoyltransferase I in cultured rat hepatocytes: spontaneous inactivation and reactivation by fatty acids. 998 83


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