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 were prepared from fat-cells isolated from rat epididymal adipose tissues of fed and 48 h-starved rats to study some aspects of fatty acid oxidation in this tissue. The data were compared with values obtained in parallel experiments with liver mitochondria that were prepared and incubated under identical conditions. 2. In the presence of malonate, fluorocitrate and arsenite, malate, but not pyruvate-bicarbonate, facilitated palmitoyl-group oxidation in both types of mitochondria. In the presence of malate, fat-cell mitochondria exhibited slightly higher rates of palmitoylcarnitine oxidation than liver. Rates of octanoylcarnitine oxidation were similar in liver and fat-cell mitochondria. Uncoupling stimulated acylcarnitine oxidation in liver, but not in fat-cell mitochondria. Oxidation of palmitoyl- and octanoyl-carnitine was partially additive in fat-cell but not in liver mitochondria. Starvation for 48 h significantly decreased both palmitoylcarnitine oxidation and latent carnitine palmitoyltransferase activity in fat-cell mitochondria. Starvation increased latent carnitine palmitoyltransferase activity in liver mitochondria but did not alter palmitoylcarnitine oxidation. These results suggested that palmitoylcarnitine oxidation in fat-cell but not in liver mitochondria may be limited by carnitine palmitoyltransferase 2 activity. 3. Fat-cell mitochondria also differed from liver mitochondria in exhibiting considerably lower rates of carnitine-dependent oxidation of palmitoyl-CoA or palmitate, suggesting that carnitine palmitoyltransferase 1 activity may severely rate-limit palmitoyl-CoA oxidation in adipose tissue.
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PMID:Some aspects of fatty acid oxidation in isolated fat-cell mitochondria from rat. 122 2

Dietary administration of 0.05, 0.1, and 0.3% LY171883 to rats for 1 day caused a dose-related increase in hepatic triglycerides. When added to rat liver mitochondria in vitro, LY171883 caused competitive inhibition of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid oxidation. This effect appears to be involved in the lipid accumulation. The hepatic triglycerides in rats given 0.1% LY171883 increased progressively through 3 months of treatment. In contrast, hepatic triglycerides in high-dose rats returned to control levels by Day 3 and remained there throughout the study. The regression of the lipid corresponded with increases in hepatic peroxisomal beta-oxidation, mitochondrial beta-oxidation, and CPT-1 activity of up to 13-, 7-, and 3.2-fold, respectively. The 0.1% dose increased these parameters modestly compared to those of high-dose rats (2-, 3-, and 1.6-fold, respectively). Addition of LY171883 to mitochondria from rats given dietary treatment for 2 weeks inhibited CPT-I by the same percentage as in control mitochondria. In mid-dose rats, the induction of CPT-I was largely negated by LY171883 in vitro. Even with the inhibition, CPT-I activity in mitochondria from high-dose rats remained 2-fold higher than that in untreated controls. The data suggest that the induction of CPT-I in high-dose rats was sufficient to overcome the inhibitory action of LY171883. The increased oxidative capacity in peroxisomes and mitochondria led to the regression of the lipid in high-dose rats. The more modest increases in fatty acid oxidation in rats given 0.1% LY171883 were not sufficient to reverse the lipid accumulation.
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PMID:Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883. 197 95

The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
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PMID:Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. 277 37

It has long been known that most of the energy production in the heart is derived from the oxidation of fatty acids. The other important sources of energy are the oxidation of carbohydrates and, to a lesser extent, ATP production from glycolysis. The contribution of these pathways to overall ATP production can vary dramatically, depending to a large extent on the carbon substrate profile delivered to the heart, as well as the presence or absence of underlying pathology within the myocardium. Despite extensive research devoted to the study of the individual pathways of energy substrate metabolism, relatively few studies have examined the integrated regulation between carbohydrate and fatty acid oxidation in the heart. While the mechanisms by which fatty acids inhibit carbohydrate oxidation (i.e., the Randle cycle) have been characterized, much less is known about how carbohydrates regulate fatty acid oxidation in the heart. It is clear that an increase in intramitochondrial acetyl-CoA derived from carbohydrate oxidation (via the pyruvate dehydrogenase complex) can downregulate beta-oxidation of fatty acids, but it is not clear how fatty acid acyl group entry into the mitochondria is downregulated when carbohydrate oxidation increases. Recent interest in our laboratory has focused on the involvement of acetyl-CoA carboxylase (ACC) in this process. While it has been known for some time that malonyl-CoA does exist in heart tissue, and that it is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT 1), it has only recently been demonstrated that an isoenzyme of ACC exists in the heart that is a potential source of malonyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The 1993 Merck Frosst Award. Acetyl-CoA carboxylase: an important regulator of fatty acid oxidation in the heart. 788 73

During hypoxia the atria from fasted rats exhibit a faster decline in the pacemaker and contractile activities than those from fed rats. Oxfenicine and methylpalmoxirate, inhibitors of carnitine palmitoyltransferase 1 (CPT 1), ameliorate these disturbances. Since the fasted rat atria have greater triacylglycerol stores and a faster lipolysis, and CPT 1 funnels fatty acid into beta-oxidation, the effects of fasting could be ascribed to the accumulation of amphipathic metabolites such as long-chain acyl CoA (LCCoA) and long-chain acylcarnitine (LCCa). Hence, this investigation aimed to assess whether the levels of these metabolites correlate with the effects of fasting and CPT 1 inhibitors. At the end of the prehypoxic equilibration period the fasted rat atria had a 6.5-fold greater content of LCCa than those of the fed rats and methylpalmoxirate impeded the increase. During hypoxia the LCCoA content increased 9-fold in the fasted rat atria, LCCa levels were 3.6-fold greater in the fasted than in the fed group, and free-CoA and free-carnitine showed a significant fall. The increases of LCCoA and LCCa as well as the fall in free-CoA were abolished by both inhibitors. The decrease of free-carnitine was impeded by methylpalmoxirate, but oxfenicine unexpectedly decreased its concentration in both nutritional groups. These data suggest that: (1) the atrial CPT 1 activity is enhanced during fasting, (2) in the hypoxic atria levels of LCCoA and LCCa were closely correlated with the noxious effects of fasting and the amelioration effected by CPT 1 inhibitors, and (3) the effects of amphipathic metabolites during oxygen deprivation can be attenuated by pharmacological interventions.
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PMID:Effects of fasting, hypoxia, methylpalmoxirate and oxfenicine on the tissue-levels of long-chain acyl CoA and acylcarnitine in the rat atria. 958 48

The rat liver carnitine palmitoyltransferase 1 (L-CPT 1) expressed in Saccharomyces cerevisiae was correctly inserted into the outer mitochondrial membrane and shared the same folded conformation as the native enzyme found in rat liver mitochondria. Comparison of the biochemical properties of the yeast-expressed L-CPT 1 with those of the native protein revealed the same detergent lability and similar sensitivity to malonyl-CoA inhibition and affinity for carnitine. Normal Michaelis-Menten kinetics towards palmitoyl-CoA were observed when careful experimental conditions were used for the CPT assay. Thus, the expression in S. cerevisiae is a valid model to study the structure-function relationships of L-CPT 1.
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PMID:Topological and functional analysis of the rat liver carnitine palmitoyltransferase 1 expressed in Saccharomyces cerevisiae. 965 May 84

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

Carnitine palmitoyltransferase I (CPT I) is one of the carnitine cycle enzymes that plays a role in the transportation of long-fatty acids into the mitochondria for beta-oxidation. Hepatic carnitine palmitoyltransferase I (CPT IA) is one of the isozymes of CPT I, and its deficiency results in an autosomal recessive mitochondrial fatty acid oxidation disorder. To date, 19 patients with CPT IA deficiency and 9 CPT IA mutations have been reported. Recently, six novel mutations in the CPT IA gene were reported in Japanese patients with CPT I deficiencies who were clinically diagnosed as having a Reye-like syndrome. One of these mutations was a missense mutation, 1079A>G (E360G). The other was a splicing mutation, 2027-2028+2delAAGT, which caused aberrant splicing transcripts, whereas 1876-2028del, 2027-2028insGTCTCTTCC ACTTCTTCC, and 2026-2028del were three aberrant transcripts that kept reading in-frame. In this report, an expression assay using SV40 transformed fibroblasts was performed to investigate the consequences of these two mutations on enzyme activity and protein levels. Molecular analysis in this study revealed that the two mutations 1079A>G and 2028+2delAAGT were the disease-causing mutations.
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PMID:Expression analysis of two mutations in carnitine palmitoyltransferase IA deficiency. 1211 67

Besides their role as energetic molecules, fatty acids (FAs) also act as signals involved in regulating gene expression. This review focuses on a few examples of FA regulation. The hepatic lipogenic enzyme, fatty acid synthase (FAS) is negatively regulated by polyunsaturated FAs (PUFAs) which suppress sterol regulatory element-binding protein 1 (SREBP 1) gene expression and nuclear content in hepatocytes, thereby reducing FAS gene transcription. It was proposed recently that this reduction in SREBP 1 was the result of a PUFA-induced antagonism of ligand-dependent activation of the liver X nuclear receptor (LXR), known to be an inducer of the SREBP 1 gene. In contrast, several genes are turned on by long-chain (LCFAs) and nonmetabolized FAs in a physiologically relevant manner. These include the acyl-CoA oxidase (AOX), the liver carnitine palmitoyltransferase 1 (L-CPT 1) and the liver fatty acid binding protein (L-FABP). While induction of AOX gene transcription appears to be PPARalpha-dependent, that of the L-CPT 1 gene seems disconnected from PPAR activation. Results obtained in preadipocytes and in intestine cells are in support of a key role played by the beta/delta isoform of PPAR in LCFA induction of the FABP gene. Transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene is stimulated by unsaturated and nonmetabolized LCFAs specifically in adipocytes. Our results reported here support the notion that the mechanisms by which PPARgamma activators and FAs induce transcription of the PEPCK gene are distinct. Altogether these data argue that several FA effects are PPAR-independent. Evidences suggesting that other transcription factors might be involved are debated. It seems now clear that depending upon the cell-specific context and the target gene, FAs can take very different routes to alter transcription.
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PMID:Is there a single mechanism for fatty acid regulation of gene transcription? 1221 84

Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic beta-cell ATP-dependent K+ (KATP) channels in the plasma membrane. This event stimulates Ca2+ influx and sets in motion the exocytotic release of insulin. However, recent reports show that >90% of glibenclamide-binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in KATP channels and cytoplasmic free Ca2+. Also, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits beta-cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and KATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated KATP-independent insulin secretion to the same extent as glibenclamide, and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches beta-cell FA metabolism to DAG synthesis and subsequent PKC-dependent and KATP-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic patients even after drug removal that contributes to the sustained hypoglycemia of the sulfonylurea.
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PMID:Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis. 1268 19


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