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.
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ABSTRACT: Enhanced biosynthesis of prostaglandin (PG)D(2) and subsequent formation of 15-deoxy-Delta(12,14)-PGJ(2) has been suggested to contribute to resolution of inflammation. The primary aim of the present study in mouse heart was, therefore, to determine at the transcriptional level if there is sequential induction of PGE and PGD synthases (S) during inflammation. Expression of interleukin (IL)-1beta in heart was enhanced 4h after systemic inflammation and declined thereafter within 3-5 days to basal levels. In contrast to cyclooxygenase-2 and membrane-bound (m)-PGES-1, which both peaked 4h after endotoxin administration, hematopoietic (H)-PGDS expression was enhanced only >or=48h after endotoxin. The expression of lipocalin-type (L)-PGDS was not significantly influenced. mRNA encoding the putative target of 15-deoxy-Delta(12,14)-PGJ(2), peroxisome proliferator-activated receptor gamma, was enhanced between 4 and 24h after induction of inflammation. Treatment of mice with acetylsalicylic acid or indomethacin at doses effective to cause near-complete inhibition of PGE(2) and PGD(2) biosynthesis in heart ex vivo resulted in enhanced expression of IL-1beta 24h after endotoxin administration. These results provide additional support for the hypothesis of a shift towards PGD(2) biosynthesis during resolution of inflammation.Biochemical and Biophysical Research Communications 09/2005; 335(3):684-9. DOI:10.1016/j.bbrc.2005.07.130 · 2.28 Impact Factor
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ABSTRACT: The use of highly active antiretroviral therapy (HAART) to manage HIV infection is associated with the development of HIV/HAART-associated dyslipidemic lipodystrophy (HADL). HADL symptoms are comprised of metabolic dysfunctions resulting in hyperlipidemia, fat redistribution, and insulin resistance. The direct interaction of HIV drugs with nuclear receptors involved in metabolic pathways has been largely unexplored. HIV drugs were evaluated for effect on the activation of farsenoid X receptor (FXR), liver X receptor alpha (LXRα), retinoid X receptor alpha (RXRα), pregnane X receptor (PXR) and the peroxisome proliferator-activated receptor family (PPAR α, γ, and δ). Our results indicate direct inhibition of PPARα and PPARγ activation by protease inhibitors (PIs) in both coactivator recruitment and reporter gene assays. Gene chip analysis demonstrated that saquinavir and ritonavir reduced the expression level of PPARγ target genes in primary human hepatocytes. Partial recovery of mRNA levels of glucokinase (GK) and GLUT2 was achieved when hepatocytes were incubated in combination with the PPARγ agonist troglitazone. Decreased glucose sensing capabilities through PI-mediated inhibition of PPARγ activation may be a contributing factor in symptoms of HADL. PPARα is the nuclear receptor responsible for regulating genes that control lipid homeostasis. Because of this role, PPARα has become a target of interest for the development of drugs to treat diseases such as dyslipidemia, obesity and atherosclerosis. Assays currently employed to determine potency and efficacy of potential drug candidates typically utilize a truncated form of the native receptor, one which lacks the entire N-terminal region of the protein. We report that differences in PPARα full length and ligand binding domain constructs result in differences in binding affinity for coactivator peptides, but have little effect on potency of agonists in both cell free and cell based nuclear receptor assays.
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ABSTRACT: It is a generally accepted paradigm that there is a direct link between inflammation and tumor progression. During inflammation, there is increased formation of lipid hydroperoxides, mediated either non-enzymatically by reactive oxygen species or enzymatically by lipoxygenases (LOs) or cyclooxygenases (COXs). Lipid hydroperoxides undergo further oxidation into oxo-eicosatetraenoic acids (oxo-ETEs), which are produced and released by cells including macrophages and epithelial cells. Therefore, these oxo-ETEs could potentially mediate biological effects in an autocrine and/or a paracrine manner. In addition, oxo-ETEs conjugate intracellular glutathione (GSH) to form adducts which could serve as biomarkers of oxo-ETE formation.In this study, a targeted lipidomics approach combined with stable isotope dilution methodology was employed to identify and quantify lipid hydroperoxides and their metabolites formed in 15-LO-expressing mouse macrophage cell line (R15L cells) and COX-2 expressing cell models (RIES cells and Caco-2 cells) as well as in mouse hematocytes and primary human monocytes. 15-Oxo-5,8,11,13-(Z,Z,Z,E)-ETE (15-oxo-ETE) was identified and characterized as a major eicosanoid produced in both mouse and human macrophage 15-LO pathway. 15-Oxo-ETE was shown to be a metabolite of arachidonic acid (AA)-derived 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). A novel biological activity of 15-oxo-ETE was revealed, which involved inhibition of human umbilical vein endothelial cell (HUVEC) proliferation by suppressing DNA synthesis, implicating a potential anti-angiogenic role of 15-oxo-ETE. In addition to 15-oxo-ETE, another AA-derived eicosanoid 11-oxo-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (11-oxo-ETE), was identified as a major metabolite arising from COX-2-derived from 11(R)-hydroxyl-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (11(R)-HETE) in both rat (RIES) and human (Caco-2) epithelial cell lines. A specific liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM/MS) method revealed that both 11-oxo-ETE and 15-oxo-ETE were secreted in nM concentrations when AA was added to RIES and human Caco-2 cells. Surprisingly, 11(R)-HETE was an excellent substrate for 15-PGDH, with a catalytic efficiency similar to that found for 15(S)-HETE. In addition, it was demonstrated that aspirin significantly stimulated the production of 15(R)-HETE, which was then converted to 15-oxo-ETE by an unknown dehydrogenase (DH). These findings could have significant clinical implications since 15-PGDH is down-regulated during carcinogenesis, which in addition to increasing the pro-proliferative activity of PGE2 would prevent the formation of anti-proliferative 15-oxo-ETE from 15(S)-HETE. However, the formation of 15-oxo-ETE from 15(R)-HETE after aspirin treatment, through a pathway that does not involve 15-PGDH, could help counteract the increased pro-proliferative activity of PGE2.