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Peroxisome proliferators include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers; this term arises because they induce an increase in the size and number of peroxisomes. Peroxisomes are subcellular organelles found in plants and animals which contain enzymes for respiration and for cholesterol and lipid metabolism. The action of peroxisome proliferators is thought to be mediated via specific receptors, called PPARs, which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear transcription factor. Multiple alternatively spliced transcript variants have been described for this gene, although the full-nature of only some have been defined. 5'-flanking region of this gene is transcriptionally active and binds PPARalpha, we characterized the peroxisome proliferator-responsive element in the proximal promoter of the CPT II gene, which appears to be a novel PPRE. A Val227Ala polymorphism in the peroxisome proliferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels. ARA70, a coactivator of the androgen receptor and PPARgamma, was identified as a ligand-enhanced coactivator of peroxisome proliferator-activated receptor alpha in a prostate cancer cell line. BF may enhance the capacity of human hepatocytes to direct PC into bile canaliculi via PPARalpha-mediated redistribution of ABCB4 to the canalicular membrane. CLOCK plays an important role in lipid homoeostasis by regulating the transcription of a key protein, PPARalpha. Data suggest that ERRalpha serves as a nodal point in the regulatory circuitry downstream of PGC-1alpha to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle. Effect of the L162V polymorphism on plasma TG and apoC-III concentrations depends on the dietary PUFA, with a high intake triggering lower TG in carriers of the 162V allele. Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Genistein activated transcriptional activity of PPARalpha in fatty acid catabolism. In humans skeletal muscle PPARalpha expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPARalpha expression in skeletal muscle. In type 2 diabetes there is a significant gene to gene interaction between the Ala55Val polymorphism in the uncoupling protein 2 gene ( UCP2) and the 161C>T polymorphism in the exon 6 of ppargamma. Increases in PGC-1 and PPAR-alpha levels may play an important role in changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin induced by endurance training. Less likely to occur in squamous cell carcinoma and actinic keratosis than in normal skin. Molecular characterisation of six alternatively spliced variants and a novel promoter in peroxisome proliferator-activated receptor alpha. Only SRC-2 serves as a true coactivator for PPARdelta, whereas all SRC members could enhance PPARalpha-induced transcriptional activation. Our findings argue against a significant contribution of PPARalpha variations to the genetic basis of psoriasis. Our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. PPAR-alpha activation increases intracellular concentrations of ROS, through the activation of NADPH oxidase. PPAR-alpha and PPAR-gamma ligands induced apoptotic and antiproliferative responses in human breast cancer cell lines, respectively, which were associated with specific changes in gene expression. PPARA L162V polymorphism is associated with increase in plasma LDL cholesterol levels. PPARA gene is a modifier of the familial combined hyperlipidemia phenotype. PPARA has a role as an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes. PPARalpha S179A-S230A protein displays an impaired ligand-induced transactivation activity and an enhanced trans-repression activity. PPARalpha and CITED2 proteins may participate in signaling cascades of hypoxic response and angiogenesis. PPARalpha and HNF-4 competitively affect the human angiotensinogen promoter through the C region. PPARalpha binding characteristics by FRET. PPARalpha binds to apolipoprotein a enhancers and influences estrogen-mediated transcription. PPARalpha gene intron variants influence age at diagnosis of typw 2 diabetes. PPARalpha has a role in CYP4X1 regulation, and the glucocorticoid and progesterone receptors have roles in CYP4Z1 gene activation. PPARalpha is one mechanism underlying the pathogenesis of hepatitis C infection. PPARalpha is regulated by fatty acids in human cells. PPARalpha protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production. PPARalpha regulates the human apolipoprotein AV gene. PPARalpha transcription factor as a major factor governing hepatic CoA levels by specific modulation of PANK1alpha gene expression. PPARalpha/RXRalpha complex was counteracted by the expression of ERRalpha in HeLa cells. Peroxisome proliferator-activated receptor (PPARalpha and PPARgamma) agonists decrease lipoprotein lipase secretion and glycated LDL uptake by human macrophages. Phe273Ala mutation dramatically reduced the binding affinity of ligands to PPARalpha; solvent effect may be concluded as the major source of the decrease of binding affinity and thereby of the decrease of its transcriptional activation activity. Response to procetofen is associated with PPARA in subjects with type 2 diabetes. TR2 and TR4 can have distinct functions. Existence of differential and bi-directional regulation between PPAR alpha and TR2/TR4. Possible roles in PPAR alpha signaling pathway in human keratinocytes. The PPAR alpha subtype localizes to the nuclear and perinuclear regions of human airway smooth muscle cells. The antiinflammatory effects of fish oil may result from the inhibitory effects of oxidized omega-3 fatty acids on NF-kappaB activation via a PPARalpha-dependent pathway. The results suggest that homocysteine may enhance vascular constrictive remodeling by inactivating PPAR-alpha and -gamma in ECs and PPAR-gamma in SMCs. There seems to be an association between the polymorphism of the PPARA gene and decreased fasting serum triglyceride levels in glucose tolerant subjects. These results identify hepatic activation of peroxisome proliferator-activated receptor-alpha as a mechanism underlying glucocorticoid-induced insulin resistance. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans. This paper focuses on the functions of PPAR-alpha in fatty acid beta-oxidation, lipid metabolism, and vascular inflammation. PPAR-alpha genetics, the clinical use of PPAR-alpha activators and their future perspective are also discussed. Variation in the PPAR gene influences human left ventricular growth in response to exercise and hypertension. Activation of PPARalpha in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma. Agonists of PPAR alpha increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription and requiring signaling through the ERK1/2 signaling pathway. CPLA(2) plays a critical role in PPAR-mediated gene transcription in HepG2 cells. Chronic treatment with the PPARalpha agonist fully prevents the acute phase response gene expression in wild-type but not in PPARalpha-deficient mice. Crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. Data contribute to a better understanding of the mechanisms by which PPARs regulate VEGF expression in bladder cancer cells. Data suggest that the PPARalpha polymorphism L162V might protect against the development of atherosclerosis or coronary heart disease in patients with diabetes mellitus type 2. Decrease in cardiac PPARalpha transcription factor gene expression observed in the failing human heart could play an important role in a reduction in fatty acid utilisation by the adult heart during cardiac hypertrophy. Differential regulation of vascular endothelial growth factor expression in bladder cancer cells (peroxisome proliferative activated receptor, beta). New cytochrome P450 1A1 induction pathway involving peroxisome proliferator-activated receptor-alpha and 2 peroxisome proliferator response element sites. Peroxisome proliferator-activated receptor alpha V162 allele is associated with reduced adiposity. Polymorphism is unrelated to schizophrenia or alcoholism. Redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha. Regulation of human ASBT gene by PPARalpha. The ligand-independent tight control of the position of the PPAR helix 12 provides an effective alternative for establishing an interaction with CoA proteins. The organization of the 5'-flanking and untranslated region of the hPPARalpha gene was characterized and the hPPARalpha promoter region has been identified. Turnover is predicted by the ubiquitin-proteasome system which controls the ligand-induced expression level of its target genes.
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