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)

Inhibition of fatty acid oxidation is well recognized as a potentially effective mechanism for controlling glycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, a direct targeting of inhibition of the intramitochondrial beta-oxidation pathway or an indirect modulation of fatty acid oxidation by inhibition of substrate release from adipose stores has been fraught with lack of efficacy, unacceptable side-effects or both. Focus has therefore recently been directed towards the carnitine palmitoyltransferase (CPT) system, a three-component system necessary for the transfer of long-chain fatty acids into the intramitochondrial matrix. This article will briefly review the background for fatty acid oxidation inhibition in NIDDM and then focus on the progress in the biological understanding and drug discovery targeting of the CPT system for the treatment of NIDDM. Based upon the review, it is concluded that mechanism-based hepatic and myocardial toxicities in normal animals and a potential for a lack of human efficacy may pose insurmountable hurdles for the development of CPT inhibitors for the treatment of NIDDM.
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PMID:Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM? 1019 30

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.
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PMID:A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. 1033 20

Two genes control expression of mitochondrial carnitine palmitoyltransferase-I (CPT-I), the enzyme that catalyzes the primary rate-controlling step in fatty acid oxidation. Two CPT-I isoforms have been found--a "liver" isoform (CPT-Ialpha) expressed in most tissues, but not in skeletal muscles, and a "muscle" isoform (CPT-Ibeta) expressed in muscles and adipocytes. Liver CPT-Ialpha increases dramatically at birth, but heart CPT-Ialpha is abundant in the fetus and diminishes at birth. Insulin, thyroid hormone, and fatty acids regulate expression of CPT-Ialpha in liver, whereas electrical stimulation increases CPT-Ibeta and decreases CPT-Ialpha in cardiac myocytes. Both genes are TATA-less and contain Sp1 transcription factor binding sites upstream of the start site of transcription. Multiple transcripts of both CPT-Ialpha and CPT-Ibeta exist, some of which may have roles in regulating fatty acid oxidation.
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PMID:Expression and regulation of carnitine palmitoyltransferase-Ialpha and -Ibeta genes. 1040 60

Plasma TGs, FFAs, and muscle TG are oxidizable lipid fuel sources for skeletal muscle metabolism during prolonged exercise. Plasma FFAs are a major fuel oxidized by skeletal muscle, and their rate of use by muscle depends on several factors, including plasma FFA availability, transport from plasma to the mitochondria, and intracellular metabolism. Mobilization of FFAs from adipose tissue is the first committed step in FFA metabolism, and it depends on the rate of adipose tissue lipolysis. Adipose tissue lipolysis increases with exercise duration and exercise intensity up to intensities of approximately 60% to 65%. Evidence suggests that FFAs are transported from plasma to the mitochondria by FFA transporter proteins that include the plasma membrane and cytosolic FABPPM and FABPC. Plasma FFA use can also be regulated at the mitochondrial transport step by changing the activity of carnitine palmitoyltransferase (CPT-1). Although results from biopsy and tracer studies indicate that muscle TG contribute to skeletal muscle oxidative metabolism during exercise, their exact contribution is difficult to ascertain. Evidence shows that muscle TG use depends on exercise intensity, duration, and mode. The contribution of plasma TG to skeletal muscle metabolism is small. The rate of use of plasma TG is dependent on lipoprotein lipase activity, which is correlated with the oxidative capacity of the muscle fibers. Dietary manipulations can modulate substrate use during exercise and can potentially affect exercise performance. High carbohydrate availability before exercise is associated with an increase in blood glucose and plasma insulin concentrations, which can ultimately decrease the rate of adipose tissue lipolysis and the availability of plasma FFAs. Increased glucose flux has also been shown to decrease lipid oxidation by directly inhibiting the transport of FFAs across the mitochondrial membranes. High lipid availability can be changed by short-term or long-term exposure to high-fat diets. Because carbohydrate reserves are diminished with exposure to high-fat diets, improvements in exercise performance have been difficult to measure under these conditions.
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PMID:Role of fats in exercise. Types and quality. 1041 Aug 36

The biochemical mechanisms responsible for basal hyperinsulinemia in insulin-resistant states have not been fully defined. We therefore studied pancreatic beta-cell function in vitro to characterize the relative importance of fuel metabolism or secretion via a constitutive pathway in the maintenance of high basal insulin secretion in Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) rats. Insulin secretion from ZF (10+/-1.8 v 5+/-0.6 pmol/ng DNA/h) and ZDF (30+/-4 v 7+/-0.8 pmol/ng DNA/h) islets at 2.8 mmol/L glucose was two to four times greater than secretion from islets of lean littermate control rats. In response to a decreasing glucose concentration (from 12 to 0 mmol/L), a paradoxical increase in insulin secretion was observed in perfused ZDF rat pancreas. Insulin secretion at 2.8 mmol/L glucose was suppressed approximately 70% to 80% in islets from ZDF and ZF rats following exposure to diazoxide, a K+-adenosine triphosphate (K(ATP)) channel opener that inhibits membrane depolarization, or rotenone and oligomycin, agents that inhibit ATP production, or by incubation at 23 degrees C. Inhibition of glycolysis with mannoheptulose, 2-deoxyglucose, and iodoacetate or fatty acid oxidation with a carnitine palmitoyltransferase I inhibitor also significantly inhibited basal insulin secretion in islets of ZDF and ZF rats but not their lean littermates. Furthermore, the glycolytic flux at 2.8 mmol/L glucose was significantly higher in ZDF islets versus ZDF lean littermate (ZLC) islets (2.2+/-0.1 v 3.7+/-0.3 pmol/ng DNA/2 h, P < .01) and was suppressed by mannoheptulose. In ZDF and ZF islets, high basal insulin secretion was maintained despite a 50% reduction in the rate of proinsulin/insulin biosynthesis at 2.8 mmol/L glucose. The rate of proinsulin to insulin conversion and the ratio of proinsulin to insulin secretion by islets of ZDF rats were similar to the values in the lean littermates. Thus, basal hypersecretion in these two insulin-resistant models appears to be related to enhanced fuel metabolism rather than the contribution of a constitutive pathway of secretion.
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PMID:Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: role of enhanced fuel metabolism. 1042 Dec 26

The aim was to establish whether increased cardiac fatty acid oxidation in hyperthyroidism is due to direct alterations in cardiac metabolism which favour fatty acid oxidation and/or whether normal regulatory links between changes in glucose supply and fatty acid oxidation are dysfunctional. Euthyroid rats were sampled in the absorptive state or after 48 h starvation. Rats were rendered hyperthyroid by injection of tri-iodothyronine (1000 microg/kg body wt. per day; 3 days). We evaluated the regulatory significance of direct effects of hyperthyroidism by measuring rates of palmitate oxidation in the absence or presence of glucose using cardiac myocytes. The results were examined in relation to the activity/regulatory characteristics of cardiac carnitine palmitoyltransferase (CPT) estimated by measuring rates of [3H]palmitoylcarnitine formation from [3H]carnitine and palmitoyl-CoA by isolated mitochondria. To define the involvement of other hormones, we examined whether hyperthyroidism altered basal or agonist-stimulated cardiac cAMP concentrations in cardiac myocytes and whether the effects of hyperthyroidism could be reversed by 24 h exposure to insulin infused subcutaneously (2 i. u. per day; Alzet osmotic pumps). Rates of 14C-palmitate oxidation (to 14CO2) by cardiac myocytes were significantly increased (1.6 fold; P< 0.05) by hyperthyroidism, whereas the percentage suppression of palmitate oxidation by glucose was greatly diminished. Cardiac CPT activities in mitochondria from hyperthyroid rats were 2-fold higher and the susceptibility of cardiac CPT activity to inhibition by malonyl-CoA was decreased. These effects were not mimicked by 48 h starvation. The decreased susceptibility of cardiac CPT activities to malonyl-CoA inhibition in hyperthyroid rats was normalised by 24 h exposure to elevated insulin concentration. Acute insulin addition did not influence the response to glucose in cardiac myocytes from euthyroid or hyperthyroid rats and basal and agonist-stimulated cAMP concentrations were unaffected by hyperthyroidism in vivo. The data provide insight into possible mechanisms by which hyperthyroidism facilitates fatty acid oxidation by the myocardium, identifying changes in cardiac CPT activity and malonyl-CoA sensitivity that would be predicted to render cardiac fatty acid oxidation less sensitive to external factors influencing malonyl-CoA content, and thereby to favour fatty acid oxidation. The increased CPT activity observed in response to hyperthyroidism may be a consequence of an impaired action of insulin but occurs through a cAMP-independent mechanism.
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PMID:Hyperthyroidism facilitates cardiac fatty acid oxidation through altered regulation of cardiac carnitine palmitoyltransferase: studies in vivo and with cardiac myocytes. 1042 24

Under hypoxic conditions the atrial contents of long-chain acyl CoA (LCCoA) and long-chain acylcarnitine display a close correlation with the noxious effects of fasting on the atrial functions as well as with the amelioration effected by inhibitors of carnitine palmitoyltransferase I. These findings suggested that fatty acid oxidation was detrimental for the hypoxic atria. However, since changes of the LCCoA and LCCa levels which may occur together with the hypoxic disturbances attained under some other metabolic interventions had not been assessed yet, present investigation aimed to provide information about this issue. At the end of the prehypoxic equilibration period, all the treatments tested evoked a fall of the free-CoA levels whereas free-carnitine, LCCoA and LCCa remained unchanged. In the hypoxic atria, 4-pentenoate, an inhibitor of fatty acid beta-oxidation that also can be oxidized, did not change LCCoA and LCCa levels whereas the readily oxidizable pentanoate evoked a drop of LCCoA. These effects may be due to the trapping of CoA as the short-chain acyl esters of both substances. Since 4-pentenoate and pentanoate were noxious on the hypoxic atria even though they did not increase LCCoA and LCCa contents, it may be inferred that short-chain acyl esters might be deleterious during oxygen shortage. The exposure to 3-hydroxybutyrate, an oxidizable substrate whose availability increases during fasting, did not alter the LCCoA and LCCa contents, agreeing with the weak detrimental effects that it exerts on the hypoxic atria. On the other hand, insulin elicited a rise in the LCCoA and a fall in the LCCa contents. Inasmuch insulin had been shown to improve the performance of the hypoxic atria, these findings suggest that LCCoA might not be involved in the noxious effects of fatty acid oxidation whereas LCCa would be the major toxic catabolite.
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PMID:Effects of pentanoate, 4-pentenoate, 3-hydroxybutyrate and insulin on the tissue-levels of long-chain acyl CoA and acylcarnitine in the oxygenated and hypoxic rat atria. 1045 55

A number of biochemical defects have been identified in glucose metabolism within skeletal muscle in obesity, and positive effects of weight loss on insulin resistance are also well established. Less is known about the capacity of skeletal muscle for the metabolism of fatty acids in obesity-related insulin resistance and of the effects of weight loss, though it is evident that muscle contains increased triglyceride. The current study was therefore undertaken to profile markers of human skeletal muscle for fatty acid metabolism in relation to obesity, in relation to the phenotype of insulin-resistant glucose metabolism, and to examine the effects of weight loss. Fifty-five men and women, lean and obese, with normal glucose tolerance underwent percutaneous biopsy of vastus lateralis skeletal muscle for determination of HADH, CPT, heparin-releasable (Hr) and tissue-extractable (Ext) LPL, CS, COX, PFK, and GAPDH enzyme activities, and content of cytosolic and plasma membrane FABP. Insulin sensitivity was measured using the euglycemic clamp method. DEXA was used to measure FM and FFM. In skeletal muscle of obese individuals, CPT, CS, and COX activities were lower while, conversely, they had a higher or similar content of FABP(C) and FABP(PM) than in lean individuals. Hr and Ext LPL activities were similar in both groups. In multivariate and simple regression analyses, there were significant correlations between insulin resistance and several markers of FA metabolism, notably, CPT and FABP(PM). These data suggest that in obesity-related insulin resistance, the metabolic capacity of skeletal muscle appears to be organized toward fat esterification rather than oxidation and that dietary-induced weight loss does not correct this disposition.
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PMID:Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. 1054 88

This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the n-3 family, play essential roles in the maintenance of energy balance and glucose metabolism. The data discussed indicate that dietary PUFA function as fuel partitioners in that they direct glucose toward glycogen storage, and direct fatty acids away from triglyceride synthesis and assimilation and toward fatty acid oxidation. In addition, the n-3 family of PUFA appear to have the unique ability to enhance thermogenesis and thereby reduce the efficiency of body fat deposition. PUFA exert their effects on lipid metabolism and thermogenesis by upregulating the transcription of the mitochondrial uncoupling protein-3, and inducing genes encoding proteins involved in fatty acid oxidation (e.g. carnitine palmitoyltransferase and acyl-CoA oxidase) while simultaneously down-regulating the transcription of genes encoding proteins involved in lipid synthesis (e.g. fatty acid synthase). The potential transcriptional mechanism and the transcription factors affected by PUFA are discussed. Moreover, the data are interpreted in the context of the role that PUFA may play as dietary factors in the development of obesity and insulin resistance. Collectively the results of these studies suggest that the metabolic functions governed by PUFA should be considered as part of the criteria utilized in defining the dietary needs for n-6 and n-3 PUFA, and in establishing the optimum dietary ratio for n-6:n-3 fatty acids.
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PMID:Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance. 1088 93

In type 2 diabetes mellitus, insulin secretory deficiency is an important process linking asymptomatic insulin resistance and diabetes. Fatty acids could play a role in the reduction of beta cell insulin secretion. On a short term basis (< 24 h), fatty acids stimulate glucose-dependent insulin secretion through an increase of ATP availability (due to acyl-CoA mitochondrial oxidation) and an extramitochondrial diacylglycerol and inositol tri phosphate (IP3) production (which stimulate insulin-containing granule exocytosis). Such effects were observed in human both in vitro and in vivo. By contrast, a chronic exposure (> 24 h) of beta cells to fatty acids leads to a reduction in glucose-dependent insulin secretion. Current explanation relies in the effect of fatty acids on beta cell gene expression through PPARs (peroxysome proliferator activated receptor). Thus, in rodents, fatty acids can increase the expression of carmitine palmitoyl transferase gene (CPT-1, the key enzyme involved in fatty acid internalization in mitochondria) while reducing the gene expression of acetyl carboxylase (this enzyme synthesis malonyl CoA, which inhibits fatty acid oxidation). Thus, a chronic exposure to fatty acids will preferentially distribute these nutrients towards mitochondria (as malonyl CoA is reduced and CPT-1 is increased), which in turn reduces their extramitochondrial metabolism as well as IP3 production that is needed for secretory granule exocytosis. Finally, in Zucker Fatty rat, diabetes is associated with a triglyceride accumulation in beta cells. This is correlated with a reduction in insulin secretion and an increase in cellular apoptosis phenomena. Thiazolidinediones prevent intracellular lipid accumulation and delay diabetes. The prevention of lipotoxicity could represent a new therapeutic strategy to preserve insulin secretion in type 2 diabetic patients.
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PMID:[Fatty acids and beta cells]. 1094 43


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