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)

Liver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4 alpha dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4 alpha and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4 alpha bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver.
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PMID:The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). 1210 81

Transcriptional regulation of carnitine palmitoyltransferase-1beta (CPT-1beta) is coordinated with contractile gene expression through cardiac-enriched transcription factors, GATA4 and SRF. Metabolic modulation of CPT-1beta promoter activity has been described with the stimulation of gene expression by oleate that is mediated through the peroxisome proliferator-activated receptor (PPAR) pathway. The coactivator, peroxisomal proliferator-activated receptor gamma coactivator (PGC-1), enhances gene expression through interactions with nuclear hormone receptors and the myocyte enhancer factor 2 (MEF2) family. PGC-1 and MEF2A synergistically activate CPT-1beta promoter activity. This stimulation is enhanced by mutation of the E-box sequences that flank the MEF2A binding site. These elements bind the upstream stimulatory factors (USF1 and USF2), which activate transcription in CV-1 fibroblasts. However, overexpression of the USF proteins in myocytes depresses CPT-1beta activity and significantly reduces MEF2A and PGC-1 synergy. Co-immunoprecipitation studies demonstrate that PGC-1 and USF2 proteins can physically interact. Our studies demonstrate that PGC-1 stimulates CPT-1beta gene expression through MEF2A. USF proteins have a novel role in repressing the expression of the CPT-1beta gene and modulating the induction by the coactivator, PGC-1.
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PMID:Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Ibeta expression by PGC-1. 1261 94

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
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PMID:Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. 1470 65

The staggerer mice carry a deletion in the RORalpha gene and have a prolonged humoral response, overproduce inflammatory cytokines, and are immunodeficient. Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-alpha-lipoproteinemia and atherosclerosis. However, relatively little is known about RORalpha in the context of target tissues, target genes, and lipid homeostasis. For example, RORalpha is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure. This lean tissue is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. In particular, the role of RORalpha in skeletal muscle metabolism has not been investigated, and the contribution of skeletal muscle to the ROR-/- phenotype has not been resolved. We utilize ectopic dominant negative RORalpha expression in skeletal muscle cells to understand the regulatory role of RORs in this major mass peripheral tissue. Exogenous dominant negative RORalpha expression in skeletal muscle cells represses the endogenous levels of RORalpha and -gamma mRNAs and ROR-dependent gene expression. Moreover, we observed attenuated expression of many genes involved in lipid homeostasis. Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. In conclusion, we speculate that ROR agonists would increase fatty acid catabolism in muscle and suggest selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis.
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PMID:RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. 1519 55

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

The PGC-1s (peroxisome-proliferator-activated receptor gamma co-activators) are a family of transcriptional regulators that induce the expression of various metabolic genes. PGC-1 proteins stimulate genes involved in mitochondrial biogenesis, fatty acid oxidation and hepatic gluconeogenesis. Previous studies have demonstrated that the PGC-1alpha and beta isoforms interact with nuclear receptors through the conserved LXXLL (leucine-X-X-leucine-leucine) motifs. In the present study, we have investigated the mechanisms by which these PGC-1 isoforms stimulate gene expression. We have determined that the N-terminus of PGC-1 is responsible for transcriptional activation. Two conserved peptide motifs were identified in the N-terminus of PGC-1alpha and beta isoforms. These domains were named AD1 and AD2 (activation domain 1 and 2). Deletion of both of these motifs decreased the induction of various PGC-1-regulated genes including the PEPCK (phosphoenolpyruvate carboxykinase) and CPT-I (carnitine palmitoyltransferase-I) genes. It was determined that amino acids containing a negative charge in AD1 and the leucine residues in AD2 were important for the transcriptional induction of the PEPCK and CPT-I genes. Disruption of the AD motifs did not diminish the ability of the PGC-1alpha protein to associate with the PEPCK or CPT-I genes. In addition, deletion of the AD domains did not eliminate the ability of PGC-1alpha to interact with the thyroid hormone receptor. The data indicate that the AD1 and AD2 motifs mediate the induction of many PGC-1- responsive genes, but they do not contribute to the recruitment of PGC-1 to target genes.
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PMID:Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor gamma co-activator (PGC-1). 1728 67

PDK4 (pyruvate dehydrogenase kinase 4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). PDC catalyzes the conversion of pyruvate to acetyl-CoA and is an important control point in glucose and pyruvate metabolism. PDK4 gene expression is stimulated by thyroid hormone (T(3)), glucocorticoids, and long chain fatty acids. The effects of T(3) on gene expression in the liver are mediated via the thyroid hormone receptor. Here, we have identified two binding sites for thyroid hormone receptor beta in the promoter of the rat PDK4 (rPDK4) gene. In addition, we have investigated the role of transcriptional coactivators and found that the PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator) enhances the T(3) induction of rPDK4. Following T(3) administration, there is an increase in the association of PGC-1 alpha with the rPDK4 promoter. Interestingly, this increased association is with the proximal rPDK4 promoter rather than the distal region of the gene that contains the T(3) response elements. Administration of T(3) to hypothyroid rats elevated the abundance of PGC-1 alpha mRNA and protein in the liver. In addition, we observed greater association of PGC-1 alpha not only with the rPDK4 gene but also with phosphoenolpyruvate carboxykinase and CPT-1a (carnitine palmitoyltransferase 1a) genes. Knockdown of PGC-1 alpha in rat hepatocytes reduced the T(3) induction of PDK4, PEPCK, and CPT-1a genes. Our results indicate that T(3) regulates PGC-1 alpha abundance and association with hepatic genes, and in turn PGC-1 alpha is an important participant in the T(3) induction of selected genes.
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PMID:Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of the peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha). 1994 29

Long chain fatty acids and pharmacologic ligands for the peroxisome proliferator activated receptor alpha (PPARalpha) activate expression of genes involved in fatty acid and glucose oxidation including carnitine palmitoyltransferase-1A (CPT-1A) and pyruvate dehydrogenase kinase 4 (PDK4). CPT-1A catalyzes the transfer of long chain fatty acids from acyl-CoA to carnitine for translocation across the mitochondrial membranes and is an initiating step in the mitochondrial oxidation of long chain fatty acids. PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway. The activity of CPT-1A is modulated both by transcriptional changes as well as by malonyl-CoA inhibition. In the liver, CPT-1A and PDK4 gene expression are induced by starvation, high fat diets and PPARalpha ligands. Here, we characterized a binding site for PPARalpha in the second intron of the rat CPT-1A gene. Our studies indicated that WY14643 and long chain fatty acids induce CPT-1A gene expression through this element. In addition, we found that mutation of the PPARalpha binding site reduced the expression of CPT-1A-luciferase vectors in the liver of fasted rats. We had demonstrated previously that CPT-1A was stimulated by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) via sequences in the first intron of the rat CPT-1A gene. Surprisingly, PGC-1alpha did not enhance CPT-1A transcription through the PPARalpha binding site in the second intron. Following knockdown of PGC-1alpha with short hairpin RNA, the CPT-1A and PDK4 genes remained responsive to WY14643. Overall, our studies indicated that PPARalpha and PGC-1alpha stimulate transcription of the CPT-1A gene through different regions of the CPT-1A gene.
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PMID:Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. 2063 86

apoE is a multi-functional protein expressed in several cell types and in several organs. It is highly expressed in adipose tissue, where it is important for modulating adipocyte lipid flux and gene expression in isolated adipocytes. In order to investigate a potential systemic role for apoE that is produced in adipose tissue, mice were generated with selective suppression of adipose tissue apoE expression and normal circulating apoE levels. These mice had less adipose tissue with smaller adipocytes containing fewer lipids, but no change in adipocyte number compared with control mice. Adipocyte TG synthesis in the presence of apoE-containing VLDL was markedly impaired. Adipocyte caveolin and leptin gene expression were reduced, but adiponectin, PGC-1, and CPT-1 gene expression were increased. Mice with selective suppression of adipose tissue apoE had lower fasting lipid, insulin, and glucose levels, and glucose and insulin tolerance tests were consistent with increased insulin sensitivity. Lipid storage in muscle, heart, and liver was significantly reduced. Adipose tissue macrophage inflammatory activation was markedly diminished with suppression of adipose tissue apoE expression. Our results establish a novel effect of adipose tissue apoE expression, distinct from circulating apoE, on systemic substrate metabolism and adipose tissue inflammatory state.
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PMID:Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation. 2542 Oct 60


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