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 induction of liver fatty acid binding protein (L-FABP) by the peroxisome proliferators bezafibrate and clofibrate was compared with the induction of peroxisomal (cyanide-insensitive) palmitoyl-CoA oxidation in cultured rat hepatocytes maintained on a substratum of laminin-rich (EHS) gel. This substratum was chosen because marked induction of both L-FABP and peroxisomal palmitoyl-CoA oxidation was effected by bezafibrate in hepatocytes supported on EHS gel, whereas only peroxisomal palmitoyl-CoA oxidation was induced in hepatocytes maintained on collagen-coated plates. In control cells on EHS, activity of peroxisomal palmitoyl-CoA oxidation remained stable, while L-FABP abundance declined with time, and L-FABP mRNA was undetectable after 5 days. In cultures exposed to bezafibrate or clofibrate, peroxisomal palmitoyl-CoA oxidation activity was induced earlier and more rapidly than L-FABP. When fibrates were withdrawn, peroxisomal palmitoyl-CoA oxidation declined rapidly, whereas L-FABP continued to increase. L-FABP induction was accompanied by a striking increase in mRNA specifying this protein. Tetradecylglycidic acid, an inhibitor of carnitine palmitoyltransferase I, effectively doubled peroxisomal palmitoyl-CoA oxidation activity. However, tetradecylglycidic acid markedly inhibited fibrate induction of L-FABP and peroxisomal palmitoyl-CoA oxidation but, unexpectedly, did not prevent the fibrate-induced proliferation of peroxisomes. Maximal induction of both L-FABP and peroxisomal palmitoyl-CoA oxidation was produced at a bezafibrate concentration in the culture medium (0.05 mM) much lower than that of clofibrate (0.3 mM). Also, bezafibrate, but not clofibrate, inhibited [1-14C]oleic acid binding to L-FABP with a Ki = 9.5 microM. We conclude that hepatocytes maintained on EHS gel provide an important tool for investigating the regulation of L-FABP. These studies show that the induction of peroxisomal beta-oxidation and L-FABP by peroxisome proliferators are temporally consecutive but closely related processes which may be dependent on a mechanism distinct from that which leads to peroxisome proliferation. Furthermore, the mechanism of action of the more potent peroxisome proliferator, bezafibrate, may be mediated, in part, by interaction of this agent with L-FABP.
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PMID:Induction of fatty acid binding protein by peroxisome proliferators in primary hepatocyte cultures and its relationship to the induction of peroxisomal beta-oxidation. 232 61

The carnitine palmitoyltransferase activity of various subcellular preparations measured with octanoyl-CoA as substrate was markedly increased by bovine serum albumin at low microM concentrations of octanoyl-CoA. However, even a large excess (500 microM) of this acyl-CoA did not inhibit the activity of the mitochondrial outer carnitine palmitoyltransferase, a carnitine palmitoyltransferase isoform that is particularly sensitive to inhibition by low microM concentrations of palmitoyl-CoA. This bovine serum albumin stimulation was independent of the salt activation of the carnitine palmitoyltransferase activity. The effects of acyl-CoA binding protein (ACBP) and the fatty acid binding protein were also examined with palmitoyl-CoA as substrate. The results were in line with the findings of stronger binding of acyl-CoA to ACBP but showed that fatty acid binding protein also binds acyl-CoA esters. Although the effects of these proteins on the outer mitochondrial carnitine palmitoyltransferase activity and its malonyl-CoA inhibition varied with the experimental conditions, they showed that the various carnitine palmitoyltransferase preparations are effectively able to use palmitoyl-CoA bound to ACBP in a near physiological molar ratio of 1:1 as well as that bound to the fatty acid binding protein. It is suggested that the three proteins mentioned above affect the carnitine palmitoyltransferase activities not only by binding of acyl-CoAs, preventing acyl-CoA inhibition, but also by facilitating the removal of the acylcarnitine product from carnitine palmitoyltransferase. These results support the possibility that the acyl-CoA binding ability of acyl-CoA binding protein and of fatty acid binding protein have a role in acyl-CoA metabolism in vivo.
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PMID:Carnitine palmitoyltransferase activities: effects of serum albumin, acyl-CoA binding protein and fatty acid binding protein. 786 1

In equine hyperkalemic periodic paralysis (HyperPP), there is evidence suggesting that the primary defect in the sodium channel is associated with a secondary alteration in triacylglycerol-associated fatty acid metabolism (TAFAM) in skeletal muscle. Furthermore, TAFAM may be involved in the therapeutic action of phenytoin. The effects of phenytoin treatment on the transcript levels of three key proteins in TAFAM, hormone sensitive lipase (HSL), carnitine palmitoyltransferase (CPT), and fatty acid binding protein (FABP), were examined. These transcripts were quantitated by competitive reverse transcription polymerase chain reaction in undifferentiated and differentiated primary cultures of equine skeletal muscle from control, heterozygous HyperPP, and homozygous-affected HyperPP horses. There was a 10-fold lower level of HSL transcript in both undifferentiated and differentiated cultures from homozygous-affected horses than from horses of the other genotypes. Phenytoin selectively increased the HSL transcript in homozygous-affected differentiated cultures to levels similar to those of the other genotypes. The levels of CPT and FABP transcripts were unaffected by genotype, differentiation, and phenytoin treatment. These results suggest that the primary defect in HyperPP may secondarily decrease HSL transcript levels and that the therapeutic action of phenytoin may include regulation of mRNA transcripts in skeletal muscle.
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PMID:Phenytoin alters transcript levels of hormone-sensitive lipase in muscle from horses with hyperkalemic periodic paralysis. 978 38

The aim of the present study was to elucidate the effects of a single dose of 3-thia fatty acids (tetradecylthioacetic acid and 3-thiadicarboxylic acid) over a 24-hr study period on the expression of genes related to peroxisomal and mitochondrial beta-oxidation in liver of rats. The plasma triglyceride level decreased at 2-4 hr, 4-8 hr, and 8-24 hr, respectively, after a single dose of 150, 300, or 500 mg of 3-thia fatty acids/kg body weight. Four to eight hours after administration of 3-thia fatty acids, a several-fold-induced gene expression of peroxisomal multifunctional protein, fatty acyl-CoA oxidase (EC 1.3.3.6), fatty acid binding protein, and 2,4-dienoyl-CoA reductase (EC 1.3.1.43) resulted, concomitant with increased activity of 2,4-dienoyl-CoA reductase and fatty acyl-CoA oxidase. The expression of carnitine palmitoyltransferase-I and carnitine palmitoyltransferase-II increased at 2 and 4 hr, respectively, although at a smaller scale. In cultured hepatocytes, 3-thia fatty acids stimulated fatty acid oxidation after 4 hr, and this was both L-carnitine- and L-aminocarnitine-sensitive. The hepatic content of eicosapentaenoic acid and docosahexaenoic acid decreased throughout the study period. In contrast, the hepatic content of oleic acid tended to increase after 24 hr and was significantly increased after repeated administration of 3-thia fatty acids. Similarly, the expression of delta9-desaturase was unchanged during the 24-hr study, but increased after feeding for 5 days. To conclude, carnitine palmitoyltransferase-I expression seemed to be induced earlier than 2,4-dienoyl-CoA reductase and fatty acid binding protein, and not later than the peroxisomal fatty acyl-CoA oxidase. The expression of delta9-desaturase showed a more delayed response.
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PMID:Early modulation of genes encoding peroxisomal and mitochondrial beta-oxidation enzymes by 3-thia fatty acids. 997 77

Decreased triacylglycerol synthesis within hepatocytes due to decreased diacylglycerol acyltransferase (DGAT) activity has been suggested to be an important mechanism by which diets rich in fish oil lower plasma triacylglycerol levels. New findings suggest that eicosapentaenoic acid (EPA), and not docosahexaenoic acid (DHA), lowers plasma triacylglycerol by increased mitochondrial fatty acid oxidation and decreased availability of fatty acids for triacylglycerol synthesis. To contribute to the understanding of the triacylglycerol-lowering mechanism of fish oil, the different metabolic properties of EPA and DHA were studied in rat liver parenchymal cells and isolated rat liver organelles. EPA-CoA was a poorer substrate than DHA-CoA for DGAT in isolated rat liver microsomes, and in the presence of EPA, a markedly lower value for the triacyl[3H]glycerol/diacyl[3H]glycerol ratio was observed. The distribution of [1-14C]palmitic acid was shifted from incorporation into secreted glycerolipids toward oxidation in the presence of EPA (but not DHA) in rat liver parenchymal cells. [1-14C]EPA was oxidized to a much greater extent than [1-14C]DHA in rat liver parenchymal cells, isolated peroxisomes, and especially in purified mitochondria. As the oxidation of EPA was more effective and sensitive to the CPT-I inhibitor, etomoxir, when measured in a combination of both mitochondria and peroxisomes, we hypothesized that both are involved in EPA oxidation, whereas DHA mainly is oxidized in peroxisomes. In rats, EPA treatment lowered plasma triacylglycerol and increased hepatic mitochondrial fatty acid oxidation and carnitine palmitoyltransferase (CPT)-I activity in both the presence and absence of malonyl-CoA. Whereas only EPA treatment increased the mRNA levels of CPT-I, DHA treatment increased the mRNA levels of peroxisomal fatty acyl-CoA oxidase and fatty acid binding protein more effectively than EPA treatment. In conclusion, EPA and DHA affect cellular organelles in relation to their substrate preference. The present study strongly supports the hypothesis that EPA, and not DHA, lowers plasma triacylglycerol by increased mitochondrial fatty acid oxidation.
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PMID:Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. 1057 60

3-Thia fatty acids are potent hypolipidemic fatty acid derivatives and mitochondrion and peroxisome proliferators. Administration of 3-thia fatty acids to rats was followed by significantly increased levels of plasma ketone bodies, whereas the levels of plasma non-esterified fatty acids decreased. The hepatic mRNA levels of fatty acid binding protein and formation of acid-soluble products, using both palmitoyl-CoA and palmitoyl-L-carnitine as substrates, were increased. Hepatic mitochondrial carnitine palmitoyltransferase (CPT) -II and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase activities, immunodetectable proteins, and mRNA levels increased in parallel. In contrast, the mitochondrial CPT-I mRNA levels were unchanged and CPT-I enzyme activity was slightly reduced in the liver. The CoA ester of the monocarboxylic 3-thia fatty acid, tetradecylthioacetic acid, which accumulates in the liver after administration, inhibited the CPT-I activity in vitro, but not that of CPT-II. Acetoacetyl-CoA thiolase and HMG-CoA lyase activities involved in ketogenesis were increased, whereas the citrate synthase activity was decreased. The present data suggest that 3-thia fatty acids increase both the transport of fatty acids into the mitochondria and the capacity of the beta-oxidation process. Under these conditions, the regulation of ketogenesis may be shifted to step(s) beyond CPT-I. This opens the possibility that mitochondrial HMG-CoA synthase and CPT-II retain some control of ketone body formation.
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PMID:Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase and carnitine palmitoyltransferase II as potential control sites for ketogenesis during mitochondrion and peroxisome proliferation. 1079 71

The presence of coconut oil in a milk replacer stimulates the growth rate of calves, suggesting a better oxidation of fatty acid in muscles. Because dietary fatty acid composition influences carnitine palmitoyltransferase I (CPT I) activity in rat muscles, this study was designed to examine the effects of a milk replacer containing either tallow (TA) or coconut oil (CO) on fatty acid utilization and oxidation and on the characteristics of intermyofibrillar (IM) and subsarcolemmal (SS) mitochondria in the heart and skeletal muscles of preruminant calves. Feeding CO did not affect palmitate oxidation rate by whole homogenates, but induced higher palmitate oxidation by IM mitochondria (+37%, P < 0.05). CPT I activity did not significantly differ between the two groups of calves. Heart and longissimus thoracis muscle of calves fed CO had higher lipoprotein lipase activity (+27% and 58%, respectively; P < 0.05) but showed no differences in fatty acid binding protein content or activity of oxidative enzymes. Whatever the muscle and the diet, IM mitochondria had higher respiration rates and enzyme activities than those of SS mitochondria (P < 0.05). Furthermore, CPT I activity of the heart was 28-fold less sensitive to malonyl-coenzyme A inhibition in IM mitochondria than in SS mitochondria. In conclusion, dietary CO marginally affected the activity of the two mitochondrial populations and the oxidative activity of muscles in the preruminant calf. In addition, this study showed that differences between IM and SS mitochondria in the heart and muscles were higher in calves than in other species studied so far.
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PMID:Dietary coconut oil affects more lipoprotein lipase activity than the mitochondria oxidative capacities in muscles of preruminant calves. 1082 46

The molecular mechanisms by which peroxisome proliferator-activated receptor (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a rat primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mitochondrial beta-oxidation. The mRNA levels of the peroxisomal beta-oxidation rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine palmitoyl transferase I (M-CPT-I), which determines the flux of mitochondrial beta-oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P = 0.001), respectively. These changes were accompanied by an increase in the transcript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0.05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermore, bezafibrate increased the mRNA levels of the fatty acid translocase (2-fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipocytes. In agreement with these changes, bezafibrate caused a 1.9-fold induction (P < 0.02) in 9,10-[(3)H]palmitate oxidation. Moreover, bezafibrate reduced the mRNA expression of several adipocyte markers, including PPARgamma (30% reduction; P = 0.05), tumor necrosis factor-alpha (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), pointing to a mobilization of fatty acids to mitochondria and peroxisomes. The reduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture of rat adipocytes also were studied in the epididymal white adipose tissue of bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increased (4.5-fold induction; P = 0.001) in epididymal white adipose tissue of bezafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold induction; P = 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, although differences in the latter were not significant because of huge individual variations. These results indicate that exposure of adipocytes to bezafibrate, independent of its hepatic effects, increases the degradation of fatty acids, reducing their availability to synthesize triglycerides. As a result, some degree of dedifferentiation of adipocytes to preadipocyte-like cells is achieved. These changes may be involved in the reduction in fat depots and in the improvement of insulin sensitivity observed after bezafibrate treatment.
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PMID:Bezafibrate reduces mRNA levels of adipocyte markers and increases fatty acid oxidation in primary culture of adipocytes. 1147 52

We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 microg.rat(-1).day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP), STZ-D rats became completely euglycemic. The effect was not seen when the same dosage was administered s.c. Centrally administered leptin did not affect peripheral insulin levels. The feeding volume of STZ-LEP rats was suppressed to the level of non-STZ-D control rats. No improvement of hyperglycemia was noted when STZ-D rats were pair-fed to match the feeding volume of STZ-LEP rats. Thus, the euglycemia of STZ-LEP rats cannot be due to the decreased feeding volume. In the STZ-D rat, glucokinase mRNA, a marker of glycolysis, is down-regulated whereas glucose-6-phosphatase mRNA, a marker of gluconeogenesis, and glucose transporter (GLUT) 2, which is implicated in the release of glucose from liver, are up-regulated. GLUT4, uncoupling protein (UCP) 1, and UCP3 were down-regulated in brown adipose tissue. These parameters returned to normal upon central infusion of leptin. GLUT4 was not down-regulated in the skeletal muscle of STZ-D rats; however, fatty acid binding protein and carnitine palmitoyltransferase I, markers for utilization and beta-oxidation of fatty acids, were up-regulated and restored when the rats were treated with leptin. The increase and subsequent decrease of fatty acid utilization suggests a decrease of glucose uptake in the skeletal muscle of STZ-D rats, which was restored upon central leptin administration. We conclude that centrally infused leptin does not control serum glucose by regulating feeding volume or elevating peripheral insulin, but by regulating hepatic glucose production, peripheral glucose uptake, and energy expenditure. The present study indicates the possibility of future development of a new class of anti-diabetic agents that act centrally and independent of insulin action.
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PMID:Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. 1191 53

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


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