Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPARalpha and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPARalpha expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans.
Mol Endocrinol 2003 Feb
PMID:Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. 1255 53

In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to diffusible growth factors and myelin-associated inhibitory molecules. Here we used an established in vivo model of adult central nervous system injury to investigate the effects of elevated cAMP on neuronal survival and axonal regeneration. We studied the effects of intraocular injections of neurotrophic factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of cAMP alone did not significantly increase RGC survival or the number of regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal regrowth, the latter effect substantially enhanced by coapplication with CPT-cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons. Neurotrophin-4/5 injections also increased RGC viability, but there was reduced long-distance axonal regrowth into grafts, an effect partially ameliorated by cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic factors to promote axonal regeneration in the injured adult mammalian central nervous system.
Mol Cell Neurosci 2003 Jan
PMID:Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. 1259 38

A number of data are consistent with the hypothesis that increases in intracellular Na+ concentration (Na+i) during ischemia and early reperfusion lead to calcium overload and exacerbation of myocardial injury. However, the mechanisms underlying the increased Na+i remain unclear. 23Na nuclear magnetic resonance spectroscopy was used to monitor Na+i in isolated rat hearts perfused with a high concentration of fatty acid as can occur under some pathological conditions. Whole-cell patch-clamp experiments were also performed on isolated cardiomyocytes in order to investigate the role of voltage-gated sodium channels. Na+i increased to substantially above control levels during no-flow ischemia. The results show that a pharmacological reduction of Na+i increase by cariporide (1 micromol/L, a Na+/H+ exchange blocker) is not the only protection against ischemia-reperfusion damage, but that such protection may also be brought about by metabolic action aimed at reducing fatty acid utilization by myocardial cells. This action was obtained in the presence of etomoxir (0.1 micromol/L), an inhibitor of carnitine palmitoyltransferase-1 (the key enzyme involved in fatty acid uptake by the mitochondria) which also decreases long-chain acyl carnitine accumulation. The possibility of Na+ channels participating in Na+i increase as a consequence of alterations in cardiac metabolism was studied in isolated cells. Sustained I(Na) was stimulated by the presence of lysophosphatidylcholine (LPC, 10 micromol/L) whose accumulation during ischemia is, at least partly, dependent on increased long-chain acyl carnitine. Current activation was particularly significant in the range of potentials between -60 and -20 mV. This may have particular relevance in ischemia. The quantity of charge carried by sustained I(Na) was reduced by 24% in the presence of 1 micromol/L cariporide. Therefore, limitation of long-chain fatty acid metabolism, and consequent limitation of ischemia-induced long-chain acyl carnitine accumulation, may contribute to reducing intracellular Na+ increase during ischemia-reperfusion.
Mol Cell Biochem 2003 Jan
PMID:Different pathways for sodium entry in cardiac cells during ischemia and early reperfusion. 1261 73

The carnitine palmitoyltransferase I (EC.2.3.1.21; CPT I) mediates the transport of fatty acids across the outer mitochondrial membrane. In mammals, there are two different proteins CPT I in the skeletal muscle (M) and liver (L) encoded by two genes. The carnitine palmitoyltransferase system of lower vertebrates received little attention. With the aim of improving knowledge on the CPT family in fish, we examined CPT I cDNA and CPT activity in different tissues of rainbow trout (Oncorhynchus mykiss). Using RT-PCR, we successfully cloned a partial CPT I cDNA sequence (1650 bp). The predicted protein sequence revealed identities of 63% and 61% with human L-CPT I and M-CPT I, respectively. This mRNA is expressed in liver, white and red skeletal muscles, heart, intestine, kidney and adipose tissue of trout. This is in good agreement with the measurement of the CPT activity in the same tissues. The [IC(50)] that reflects the sensitivity to malonyl-CoA inhibition was 0.116+/-0.004 microM for the liver and 0.426+/-0.041 microM for the white muscle. These results demonstrate for the first time the existence of at least one gene encoding for CPT I present in both the liver and the muscle of rainbow trout.
Comp Biochem Physiol B Biochem Mol Biol 2003 May
PMID:Cloning and tissue distribution of a carnitine palmitoyltransferase I gene in rainbow trout (Oncorhynchus mykiss). 1278 81

The purpose of this study was to investigate the effects of altering relative intakes of fat and carbohydrates on serum lipid profiles, hepatic acyl-CoA synthetase (ACS), carnitine palmitoyltransferase-I (CPT-I), and the acetyl-CoA carboxlyase (ACC) mRNA level in Sprague-Dawley rats. For four weeks the rats were fed either an AIN-76 diet or one of its modified diets that were supplemented with 20% beef tallow (high-fat diet, HF) and 66.3% sucrose (high-sucrose diet, HS). The HS group had significantly higher serum triglyceride and total cholesterol concentrations when compared with the other groups. Serum LDL-cholesterol concentrations in the HS and HF groups were significantly higher when compared to the normal diet (ND) group. Serum HDL-cholesterol levels of the ND and HS groups were significantly higher than those of the HF group. The hepatic total lipid level of the HF group was significantly higher than those of other groups; triglyceride levels of the HS and HF groups were significantly higher than those of the ND group. Hepatic ACS mRNA levels of the HF group were significantly higher than those of the ND group. Hepatic CPT-I mRNA levels were higher in the HF group than other groups. Also, ACC mRNA levels in the liver increased in the HF group. In conclusion, changes in the composition of dietary fat and carbohydrates could affect the hepatic ACS, CPT-I, and ACC mRNA levels. These results facilitate our understanding of the coordinated regulation of the ACS, CPT-I, and ACC mRNA levels and will serve to enhance our understanding of the molecular mechanisms that underlie the regulation of fatty acid metabolism.
J Biochem Mol Biol 2003 May 31
PMID:The effects of a high-fat or high-sucrose diet on serum lipid profiles, hepatic acyl-CoA synthetase, carnitine palmitoyltransferase-I, and the acetyl-CoA carboxylase mRNA levels in rats. 1278 88

Changes in key enzymes of oxidative metabolism at the mitochondrial level are known to be associated with the aging process, apoptosis, and many diseases. Considering the risk of acquiring a myelodysplastic syndrome (MDS) with age, the aim of this study was to quantify mRNA synthesis of the carnitine palmitoyltransferases (CPT1 and CPT2), carnitine acetyltransferase (CRAT), human specific microsomal CPT, and OCTN2 (organic cation transporter) in mononuclear cells of healthy humans of different age groups and MDS patients. Using quantitative reverse transcriptase real-time PCR we compared mRNA synthesis of the above mentioned enzymes in mononuclear cells from peripheral blood of 23 healthy persons (mean age 45 years), 9 blood and 22 bone marrow samples of 31 MDS patients with varying proportions of apoptotic cells (mean age 78 years), and blood samples of 30 age-matched controls. In addition, plasma carnitine levels were determined. Compared to younger adults, there was a 50% downregulation of CPT1 in elderly persons and in MDS patients. Reduction in CRAT, CPT 2, and OCTN2 was more than 85%. Reduction in microsomal CPT was more pronounced in MDS patients than in age-matched controls (96% vs. 43%). In MDS bone marrow cells there was a negative correlation of CPT1 and CRAT with the relative proportion of apoptotic cells. Plasma carnitine values were similar in all groups. The described reduction in transcription of different genes in blood cells which is well known in different tissues may reflect a systemic signaling process, associated with aging, apoptosis, and MDS.
J Mol Med (Berl) 2003 Jul
PMID:Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. 1280 1

We report the first splice junction mutation to be described in the carnitine palmitoyltransferase (CPT) 2 gene in a patient with the muscle form of CPT II deficiency. The patient, a 25-year-old man, suffered from attacks of myalgia and muscle weakness in early adult life. There was biochemical evidence of CPT II deficiency. Molecular genetic analysis revealed the common S113L mutation on one allele whilst a novel mutation at the splice donor junction in intron 3 was identified on the other allele. Sequencing of reverse transcription polymerase chain reaction (RT-PCR) products clearly demonstrated that this mutation causes the skipping of exon 3, thus establishing its pathogenic role.
Mol Genet Metab 2003 Jun
PMID:A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency. 1280 43

I(f) contributes to generation and autonomic control of spontaneous activity of cardiac pacemaker cells through a cAMP-dependent, Ca(2+)-independent mechanism of rate regulation. However, disruption of Ca(2+) release from sarcoplasmic reticulum (SR) by ryanodine (Ry) has been recently shown to slow spontaneous rate and inhibit beta-adrenergic receptor (betaAR)-induced rate acceleration, leading to the suggestion that the target of betaAR modulation of pacemaking is the intracellular Ca(2+)-regulatory process. We have investigated whether the Ry-induced decrease of betaAR rate modulation alternatively involves disruption of the betaAR-adenylate-cyclase-cAMP-I(f) mechanism. Prolonged exposure to Ry (3 microM, >2 min) slowed spontaneous rate of pacemaker cells by 29.8% via a depolarizing shift of take-off potential (TOP) without significantly changing early diastolic depolarization rate. Ry depressed rate acceleration caused by isoproterenol (Iso) (1 microM, 23.6% in control vs. 8.0%), but did not modify that caused by two membrane-permeable cAMP analogs, CPT-cAMP (300 microM, 17.7% vs. 17.3%) and Rp-cAMPs (50 microM, 18.0% vs. 20.6%). Consistent with the rate effect, exposure to Ry decreased the shift induced by Iso, but not that induced by either cAMP analog on the I(f)-activation curve. We conclude that disruption of Ry receptor function and SR Ca(2+) release depresses betaAR-induced modulation of heart rate, but does not impair cAMP-dependent rate acceleration mediated by I(f). However, abolishment of normal Ca(2+) homeostasis may result in the failure of betaAR agonists to sufficiently elevate cAMP near f-channels. The molecular basis for Ca(2+)-dependent interference in beta-adrenergic signaling remains to be determined.
J Mol Cell Cardiol 2003 Aug
PMID:I(f)-dependent modulation of pacemaker rate mediated by cAMP in the presence of ryanodine in rabbit sino-atrial node cells. 1287 75

This study examined the actions of 17beta-estradiol (E(2)) and progesterone on the regulation of the peroxisome proliferator-activated receptors (PPARalpha and PPARgamma) family of nuclear transcription factors and the mRNA abundance of key enzymes involved in fat oxidation, in skeletal muscle. Specifically, carnitine palmitoyltransferase I (CPT I), beta-3-hydroxyacyl CoA dehydrogenase (beta-HAD), and pyruvate dehydrogenase kinase 4 (PDK4) were examined. Sprague-Dawley rats were ovariectomized and treated with placebo (Ovx), E(2), progesterone, or both hormones in combination (E+P). Additionally, sham-operated rats were treated with placebo (Sham) to serve as controls. Hormone (or vehicle only) delivery was via time release pellets inserted at the time of surgery, 15 days prior to analysis. E(2) treatment increased PPARalpha mRNA expression and protein content (P<0.05), compared with Ovx treatment. E(2) also resulted in upregulated mRNA of CPT I and PDK4 (P<0.05). PPARgamma mRNA expression was also increased (P<0.05) by E(2) treatment, although protein content remained unaltered. These data demonstrate the novel regulation of E(2) on PPARalpha and genes encoding key proteins that are pivotal in regulating skeletal muscle lipid oxidative flux.
J Mol Endocrinol 2003 Aug
PMID:17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle. 1291 23

Cardiac expression of genes involved in fatty acid metabolism may suffer alterations depending on the substrate availability. We studied how troglitazone, an antidiabetic drug that selectively activates peroxisome proliferator-activated receptor gamma (PPARgamma), affected the expression of several of these genes. A single-day troglitazone administration (100 mg/kg/day) did not significantly alter plasma free fatty acids or triglyceride levels. In contrast, a 10-day period of troglitazone treatment significantly reduced plasma free fatty acids and triglyceride levels by 74% (P < 0.001) and 56% (P < 0.01), respectively. Cardiac mRNA expression of acyl-CoA oxidase (ACO) increased (8.3-fold induction) after 1-day troglitazone treatment, whereas after 10 days of treatment ACO mRNA levels were dramatically reduced (98% reduction, P < 0.02), as well as those of uncoupling protein 3 (41% reduction, P = 0.05). The mRNA expression of PPARalpha and several PPAR target genes, such as medium chain acyl-CoA dehydrogenase or fatty acid translocase were not altered after 10 days of troglitazone treatment, whereas muscle-type carnitine palmitoyltransferase I increased 1.7-fold (P < 0.05). The reduction in ACO expression in the hearts of 10-day troglitazone-treated mice was accompanied by an increase in the protein levels of the transcriptional repressor chicken ovalbumin upstream promoter transcription factor II (COUP-TF II). Electrophoretic mobility shift assays performed with COUP-TF II antibody to examine its interaction with a labeled peroxisome proliferator response element probe showed enhanced binding of COUP-TFII in cardiac nuclear extracts from troglitazone-treated mice for 10 days but not in the control nuclear extracts. Overall, the findings presented here show that 10 days of troglitazone treatment decreased expression of the ACO gene through a mechanism involving the transcriptional repressor COUP-TF II.
Mol Pharmacol 2003 Sep
PMID:Down-regulation of acyl-CoA oxidase gene expression in heart of troglitazone-treated mice through a mechanism involving chicken ovalbumin upstream promoter transcription factor II. 1292 Feb 14


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