Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We have previously shown that metoprolol decreases carnitine palmitoyltransferase-1 (CPT-1) activity, a mechanism which may partly explain its beneficial effects in heart failure. It is possible that this effect occurs as a result of repression of cardiac CPT-1B expression. CPT-1B is induced by the transcription factors peroxisome proliferator activated receptor-alpha (PPAR-alpha) and PPAR-gamma-coactivator 1alpha (PGC1alpha) and repressed by upstream stimulatory factor-2 (USF-2). We therefore hypothesized that metoprolol represses CPT-1B by increasing USF-2-mediated repression of PGC1alpha. Male Wistar Rats were divided into 4 groups: control, control treated with metoprolol for 5 weeks, diabetic and diabetic treated with metoprolol for 5 weeks. After termination, the expression of CPT-1 isoforms, PPAR-alpha, PGC1alpha USF-1 and USF-2, as well as downstream targets were measured. Binding of PPAR-alpha, PGC1alpha and USF-2 to PGC1alpha was measured using coimmunoprecipitation. The occupation of PPAR-alpha and MEF-2A consensus sites in the CPT-1B promoter was measured using chromatin immunoprecipitation assays. Chronic metoprolol treatment decreased the expression of CPT-1B in diabetic hearts. The expression of USF-2 was increased by metoprolol in both control and diabetic hearts, but the association of USF-2 with PGC1alpha was increased by metoprolol only in diabetic hearts. Metoprolol prevented the increase in PGC1alpha occupation of the CPT-1B promoter region observed in the diabetic heart without affecting PPAR-alpha occupation. Metoprolol decreases CPT-1B expression by decreasing PGC1alpha-mediated coactivation of PPAR-alpha and MEF-2A. This is associated with increased PGC1alpha/ USF-2 binding, suggesting that USF-2 mediates the metoprolol-induced repression of PGC1alpha.
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PMID:Metoprolol represses PGC1alpha-mediated carnitine palmitoyltransferase-1B expression in the diabetic heart. 1923 64

The cardiac-enriched isoform of acetyl-CoA carboxylase (ACCbeta) produces malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase-1. AMPK inhibits ACCbeta activity, lowering malonyl-CoA levels and promoting mitochondrial fatty acid beta-oxidation. Previously, AMPK increased promoter binding of nuclear respiratory factor-1 (NRF-1), a pivotal transcriptional modulator controlling gene expression of mitochondrial proteins. We therefore hypothesized that NRF-1 inhibits myocardial ACCbeta promoter activity via AMPK activation. A human ACCbeta promoter-luciferase construct was transiently transfected into neonatal cardiomyocytes+/-a NRF-1 expression construct. NRF-1 overexpression decreased ACCbeta gene promoter activity by 71+/-4.6% (p<0.001 vs. control). Transfections with 5'-end serial promoter deletions revealed that NRF-1-mediated repression of ACCbeta was abolished with a pPIIbeta-18/+65-Luc deletion construct. AMPK activation dose-dependently reduced ACCbeta promoter activity, while NRF-1 addition did not further decrease it. We also investigated NRF-1 inhibition in the presence of upstream stimulatory factor 1 (USF1), a known transactivator of the human ACCbeta gene promoter. Here NRF-1 blunted USF1-dependent induction of ACCbeta promoter activity by 58+/-7.5% (p<0.001 vs. control), reversed with a dominant negative NRF-1 construct. NRF-1 also suppressed endogenous USF1 transcriptional activity by 55+/-6.2% (p<0.001 vs. control). This study demonstrates that NRF-1 is a novel transcriptional inhibitor of the human ACCbeta gene promoter in the mammalian heart. Our data extends AMPK regulation of ACCbeta to the transcriptional level.
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PMID:AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase: Role of nuclear respiratory factor-1. 2059 96