Activation of nuclear receptors by prostaglandins.
ABSTRACT Deletion of membrane receptors for prostaglandins has revealed their importance in diverse biological systems. Some evidence has accrued to support the contention that they may also ligate nuclear receptors, particularly peroxisomal proliferator activator receptors (PPARs). This is most pronounced in the case of 15-deoxy PGJ2, a cyclopentanone derivative of PGJ2 as a ligand for PPARgamma. However, while this compound can ligate the PPAR, the quantities formed in vivo suggest that this is an unlikely endogenous ligand. Furthermore, biosynthesis is unaltered in murine atherosclerosis and other inflammatory and metabolic disorders where activation of this PPAR has been implicated. The suggestion that prostaglandins serve as endogenous ligands for nuclear receptors is presently configured on the use of synthetic compounds and immunoreactive quantitation of dubious validity. The application of quantitatively precise and sensitive physicochemical methodology will enhance experiments designed to address this hypothesis.
- Journal of Clinical Biochemistry and Nutrition 01/2005; 37(2):39-44. · 2.29 Impact Factor
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ABSTRACT: Aim: The aim of the study was to estimate the influence of interactions between peroxisome proliferator-activated receptor γ (PPARγ) and target genes lipoprotein lipase (LPL), interleukin 6 (IL6), angiotensin converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) on metabolic syndrome (MetSy) and its traits. Methods: The study included 527 participants (263 with MetSy and 264 controls). Genotyping of PPARγ Pro12Ala, LPL PvuII (-/+), IL6 -174G>C, ACE I/D and AT1R 1166A>C was performed using polymerase chain reaction-restriction fragment length polymorphism-based methods. Results: Interaction between PPARγ Pro12Ala and LPL Pvu(-/+) improved prediction of MetSy over and above prediction based on a model containing no interactions (χ(2)=7.22; df=1; p=0.007). In the group of participants with PPARγ Pro12Ala or Ala12Ala genotypes, those with the LPL Pvu (-/+) or (+/+) genotype had greater odds for MetSy (odds ratio OR=5.98; 95% confidence interval CI: 1.46-24.47, p=0.013). Interaction between PPARγ Pro12Ala and IL6 -174G>C improved prediction of high fasting blood glucose (χ(2)=13.99; df=1; p<0.001). PPARγ Ala12 variant was found protective in patients with IL6 -174GG genotype (OR=0.10; 95% CI: 0.02-0.57, p=0.01), while in the case of IL6 -174C allele carriers, for PPARγ Ala12 carriers, larger odds for high glucose levels compared with Pro12 variant were observed (OR=2.39; 95% CI: 1.11-5.17, p=0.026). Interactions of PPARγ and ACE were significant for BMI. In the group with ACE DD genotype, those with PPARγ Pro12Ala or Ala12Ala genotype have greater odds for obesity (OR=9.98; 95% CI: 1.18-84.14, p=0.034). Conclusions: PPARγ gene variants can, in interaction with some of its target genes, modulate physiological processes leading to the development of MetSy.Genetic Testing and Molecular Biomarkers 11/2013; · 1.44 Impact Factor
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ABSTRACT: Cyclooxygenases (COXs) metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETEs), which can then be oxidized by dehydrogenases such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to oxo-eicosatetraenoic acids (ETEs). We have previously established that 11-oxo-eicosatetraenoic acid (oxo-ETE) and 15-oxo-ETE are major COX-2/15-PGDH-derived metabolites. Stable isotope dilution chiral liquid chromatography coupled with electron capture atmospheric pressure chemical ionization/mass spectrometry has now been used to quantify uptake of 11-oxo-ETE and 15-oxo-ETE in both human umbilical vein endothelial cells (HUVECs) and LoVo cells. Intracellular 11-oxo- and 15-oxo-ETE reached maximum levels within 1 h and declined rapidly, with significant quantitative differences in uptake between lines. The methyl-esters of both 11-oxo- and 15-oxo-ETE significantly increased the intracellular pool of the corresponding free oxo-ETEs. 11-oxo-ETE, 15-oxo-ETE, and their methyl esters inhibited proliferation in both HUVECs and LoVo cells where 11-oxo-ETE methyl ester was the most potent. Co-treatment with probenecid, an inhibitor of multiple drug resistance transporters (MRPs) 1 and 4, increased the anti-proliferative effect of 11-oxo-ETE methyl ester and increased recovery of 11-oxo-ETE from treated LoVo cells. Therefore, the present study has established that the COX-2/15-PGDH derived eicosanoids 11-oxo- and 15-oxo-ETE enter target cells, that they inhibit cellular proliferation, and that their inhibitory effects are modulated by MRP exporters.The Journal of Lipid Research 08/2013; · 4.73 Impact Factor