The human peroxisome proliferator-activated receptor ?? gene: identification and functional characterization of two natural allelic variants

Sapone, Andrea; Peters, Jeffrey M.; Sakai, Shuichi; Tomita, Shuhei; Papiha, S. S.; Dai, Renke; Friedman, Fred K.; Gonzalez, Frank J.

doi:10.1097/00008571-200006000-00006

Cited by 118 publications

(103 citation statements)

References 56 publications

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“…However, the L162V polymorphism has different effects on gene transcription depending on the concentration of ligand. In the presence of high concentrations, transcriptional activity of the G (162V) allele is higher compared with that of the C allele (8,20), whereas at low concentrations results are the opposite (20). In our study and a previous study (10) the presence of the G (162V) allele increased the risk of diabetes.…”

Section: Discussionsupporting

confidence: 46%

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Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Andrulionytė

Kuulasmaa²,

Chiasson³

et al. 2007

Diabetes

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for the STOP-NIDDM Study Group* Peroxisome proliferator-activated receptor (PPAR) ␣, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-␣ gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-␥2, PPAR-␥ coactivator 1␣, and hepatic nuclear factor 4␣ genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7-and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-␣. Diabetes

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Section: Discussionsupporting

confidence: 46%

“…rs1800206 of PPARA is likely to be functional. Transcriptional studies have demonstrated that the C to G change in codon 162 (L162V) of exon 5 encodes a more active PPAR-␣ in vitro (8,20). However, the L162V polymorphism has different effects on gene transcription depending on the concentration of ligand.…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Andrulionytė

Kuulasmaa²,

Chiasson³

et al. 2007

Diabetes

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“…The PPARa is a nuclear hormone receptor with a cysteine-rich zinc finger DNA-binding region. Cloning and sequencing of the gene identified two non-synonymous SNPs in the DNA-binding domain (139). Leu162Val which is normally conserved between species, makes the protein unresponsive to low ligand concentrations compared to the wildtype, whilst the mutant allele has also been associated with higher plasma total and low-density lipoprotein (LDL)-apolipoprotein B and LDL-cholesterol in a FrenchCanadian population (140).…”

Section: Ltb 4 Receptors and Pparamentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

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“…Several polymorphisms of the human PPAR␣ gene have been described recently (46 -48). Of these, the L162V variant showed decreased non-ligand-dependent transactivation activity and decreased sensitivity to low concentrations of ligand in tissue culture experiments (46). In human studies, it was reported to be associated with elevated plasma low density lipoprotein concentration and increased risk for atherosclerosis and ischemic heart disease (33,47,48).…”

Section: Controlmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

Fischer

You

Matsumoto

et al. 2003

Journal of Biological Chemistry

274

196

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Proper function of the peroxisome proliferator-activated receptor ␣ (PPAR␣) is essential for the regulation of hepatic fatty acid metabolism. Fatty acid levels are increased in liver during the metabolism of ethanol and should activate PPAR␣. However, recent in vitro data showed that ethanol metabolism inhibited the function of PPAR␣. We now report that ethanol feeding impairs fatty acid catabolism in the liver in part via blocking PPAR␣-mediated responses in C57BL/6J mice. Ethanol feeding decreased PPAR␣/retinoid X receptor ␣ binding in electrophoretic mobility shift assay of liver nuclear extracts. mRNAs for PPAR-regulated genes were reduced (long chain and medium chain acyl-CoA dehydrogenases) or failed to be induced (acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase, very long chain acyl-CoA synthetase, very long chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals, and ethanol feeding did not increase the rate of fatty acid ␤-oxidation. Wy14,643, a PPAR␣ agonist, restored the DNA binding activity of PPAR␣/retinoid X receptor ␣, induced mRNA levels of PPAR␣ target genes, stimulated the rate of fatty acid ␤-oxidation, and prevented fatty liver in ethanol-fed animals. Impairment of PPAR␣ function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by Wy14,643.

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The human peroxisome proliferator-activated receptor ?? gene: identification and functional characterization of two natural allelic variants

Cited by 118 publications

References 56 publications

Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Leukotriene pathway genetics and pharmacogenetics in allergy

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

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