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)

To examine the signals regulating cardiac growth and molecular structure of subcellular organelles, cardiac hypertrophy was induced in rats by constriction of the abdominal aorta for 12-13 wk or by treatment with a carnitine palmitoyltransferase I inhibitor, etomoxir (12-15 mg/kg body wt) for 12-13 wk. In contrast to pressure overload, etomoxir redistributed the myosin isozyme population from V3 to V1 and increased the sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase activity. When rats with pressure-overloaded hearts were treated with etomoxir, the cardiac hypertrophy was increased whereas the shift in myosin isozymes from V1 to V3 was prevented and the depression in SR Ca(2+)-stimulated ATPase activity was reversed. Plasma thyroid hormone and insulin concentrations were not altered but triglyceride concentrations were reduced in etomoxir-treated rats with pressure overload. The data demonstrate a dissociation between cardiac muscle growth and changes in subcellular organelles and indicate that a shift in myocardial substrate utilization may represent an important signal for molecular remodeling of the heart.
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PMID:Modification of subcellular organelles in pressure-overloaded heart by etomoxir, a carnitine palmitoyltransferase I inhibitor. 153 68

This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease.
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PMID:Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states. 390 84

To study the regulation of carnitine palmitoyltransferase-I by thyroid hormone, a cDNA was obtained by PCR amplification of DNA obtained by reverse transcription of rat liver RNA. CPT-I mRNA abundance was measured in livers of hyperthyroid, euthyroid and hypothyroid rats. In hypothyroid rats, the CPT-I mRNA levels decreased 40-fold relative to that of the hyperthyroid animals. These changes paralleled alterations in enzyme activity. These data suggest that CPT-I is regulated at the transcriptional level by thyroid hormone.
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PMID:Changes in carnitine palmitoyltransferase-I mRNA abundance produced by hyperthyroidism and hypothyroidism parallel changes in activity. 800 33

It is known that thyroid hormone enhances the biosynthesis of phosphatidylcholine in the lung. The purpose of the present study was to investigate the effects of thyroid hormone on the activity of cholinephosphotransferase, the terminal enzyme in the CDP-choline pathway, in guinea pig lung mitochondria and microsomes. Intramuscular injection of triiodothyronine (T3, 0.25-4 mg/kg body wt) stimulated the activities of both mitochondrial and microsomal enzymes in a dose-dependent manner. However, the stimulation was much more pronounced in the microsomes than in the mitochondria. The stimulatory effect of T3 was blocked by the intraperitoneal injection of both actinomycin D and cycloheximide in the microsomes, whereas in the mitochondria, the hormonal effect was blocked only by cycloheximide. Thus, it is suggested that T3 stimulates not only the nucleocytoplasmic system for the de novo synthesis of the enzyme, but possibly also the regulation of the transport of the synthesized protein into the mitochondria. Furthermore, administration of T3 produced an increase in the uptake and incorporation of [14C]choline into phospholipids of lung slices in vitro. However, this effect was blocked by intraperitoneal injection of both actinomycin D and cycloheximide. Thus, the change in CPT activity by T3 in mitochondria is not reflected by enhanced incorporation of choline into phosphatidylcholine.
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PMID:Role of thyroid hormone in de novo synthesis of cholinephosphotransferase in guinea pig lung mitochondria and microsomes. 828 14

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

Carnitine palmitoyltransferase I (CPT-I) catalyzes the transfer of long chain fatty acyl groups from CoA to carnitine for translocation across the mitochondrial inner membrane. CPT-Ialpha is a key regulatory enzyme in the oxidation of fatty acids in the liver. CPT-Ialpha is expressed in all tissues except skeletal muscle and adipose tissue, which express CPT-Ibeta. Expression of CPT-Ialpha mRNA and enzyme activity are elevated in the liver in hyperthyroidism, fasting, and diabetes. CPT-Ialpha mRNA abundance is increased 40-fold in the liver of hyperthyroid compared with hypothyroid rats. Here, we examine the mechanisms by which thyroid hormone (T3) stimulates CPT-Ialpha gene expression. Four potential T3 response elements (TRE), which contain direct repeats separated by four nucleotides, are located 3000-4000 base pairs 5' to the start site of transcription in the CPT-Ialpha gene. However, only one of these elements functions as a TRE. This TRE binds the T3 receptor as well as other nuclear proteins. Surprisingly, the first intron of the CPT-Ialpha gene is required for the T3 induction of CPT-Ialpha expression, but this region of the gene does not contain a TRE. In addition, we show that CPT-Ialpha is induced by T3 in cell lines of hepatic origin but not in nonhepatic cell lines.
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PMID:Thyroid hormone regulates carnitine palmitoyltransferase Ialpha gene expression through elements in the promoter and first intron. 1095 41

Carnitine palmitoyltransferase-I (CPT-I) catalyzes the rate-controlling step of fatty acid oxidation. CPT-I converts long-chain fatty acyl-CoAs to acylcarnitines for translocation across the mitochondrial membrane. The mRNA levels and enzyme activity of the liver isoform, CPT-Ialpha, are greatly increased in the liver of hyperthyroid animals. Thyroid hormone (T3) stimulates CPT-Ialpha transcription far more robustly in the liver than in non-hepatic tissues. We have shown that the thyroid hormone receptor (TR) binds to a thyroid hormone response element (TRE) located in the CPT-Ialpha promoter. In addition, elements in the first intron participate in the T3 induction of CPT-Ialpha gene expression, but the CPT-Ialpha intron alone cannot confer a T3 response. We found that deletion of sequences in the first intron between +653 and +744 decreased the T3 induction of CPT-Ialpha. Upstream stimulatory factor (USF) and CCAAT enhancer binding proteins (C/EBPs) bind to elements within this region, and these factors are required for the T3 response. The binding of TR and C/EBP to the CPT-Ialpha gene in vivo was shown by the chromatin immunoprecipitation assay. We determined that TR can physically interact with USF-1, USF-2, and C/EBPalpha. Transgenic mice were created that carry CPT-Ialpha-luciferase transgenes with or without the first intron of the CPT-Ialpha gene. In these mouse lines, the first intron is required for T3 induction as well as high levels of hepatic expression. Our data indicate that the T3 stimulates CPT-Ialpha gene expression in the liver through a T3 response unit consisting of the TRE in the promoter and additional factors, C/EBP and USF, bound in the first intron.
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PMID:A thyroid hormone response unit formed between the promoter and first intron of the carnitine palmitoyltransferase-Ialpha gene mediates the liver-specific induction by thyroid hormone. 1249 35

Carnitine palmitoyltransferase I (CPT-I) catalyzes the rate-controlling step in the pathway of mitochondrial fatty acid oxidation. Thyroid hormone will stimulate the expression of the liver isoform of CPT-I (CPT-I alpha). This induction of CPT-I alpha gene expression requires the thyroid hormone response element in the promoter and sequences within the first intron. The peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a coactivator that promotes mitochondrial biogenesis, mitochondrial fatty acid oxidation, and hepatic gluconeogenesis. In addition, PGC-1 alpha will stimulate the expression of CPT-I alpha in primary rat hepatocytes. Here we report that thyroid hormone will increase PGC-1 alpha mRNA and protein levels in rat hepatocytes. In addition, overexpression of PGC-1 alpha will enhance the thyroid hormone induction of CPT-I alpha indicating that PGC-1 alpha is a coactivator for thyroid hormone. By using chromatin immunoprecipitation assays, we show that PGC-1 alpha is associated with both the thyroid hormone response element in the CPT-I alpha gene promoter and the first intron of the CPT-I alpha gene. Our data demonstrate that PGC-1 alpha participates in the stimulation of CPT-I alpha gene expression by thyroid hormone and suggest that PGC-1 alpha is a coactivator for thyroid hormone.
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PMID:Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha). 1546 41

The peroxisome proliferator activated receptor gamma coactivators (PGC-1) have important roles in mitochondrial biogenesis and metabolic control in a variety of tissues. There are multiple isoforms of PGC-1 including PGC-1alpha and PGC-1beta. Both the PGC-1alpha and beta isoforms promote mitochondrial biogenesis and fatty acid oxidation, but only PGC-1alpha stimulates gluconeogenesis in the liver. Carnitine palmitoyltransferase I (CPT-I) is a key enzyme regulating mitochondrial fatty acid oxidation. In these studies, we determined that PGC-1beta stimulated expression of the "liver" isoform of CPT-I (CPT-Ialpha) but that PGC-1beta did not induce pyruvate dehydrogenase kinase 4 (PDK4) which is a regulator of pyruvate metabolism. The CPT-Ialpha gene is induced by thyroid hormone. We found that T3 increased the expression of PGC-1beta and that PGC-1beta enhanced the T3 induction of CPT-Ialpha. The thyroid hormone receptor interacts with PGC-1beta in a ligand dependent manner. Unlike PGC-1alpha, the interaction of PGC-1beta and the T3 receptor does not occur exclusively through the leucine-X-X-leucine-leucine motif in PGC-1beta. We have found that PGC-1beta is associated with the CPT-Ialpha gene in vivo. Overall, our results demonstrate that PGC-1beta is a coactivator in the T3 induction of CPT-Ialpha and that PGC-1beta has similarities and differences with the PGC-1alpha isoform.
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PMID:Regulation of carnitine palmitoyltransferase I (CPT-Ialpha) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms. 1723 28

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4alpha (HNF-4alpha) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4alpha levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T(3)) and thyroxine (T(4))) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T(4) treatment of HepG2 cells for 5 days increased HNF-4alpha mRNA and HNF-4alpha levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T(3) along with increased hepatic HNF-4alpha levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T(4) treatment, but a 4-day pre-treatment with T(4) resulted in a robust response that was prevented by co-treatment with HNF-4alpha siRNA, or by blocking the beta-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4alpha gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4alpha levels in hepatocytes.
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PMID:Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha. 1933 34


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