Activation of nuclear receptors by prostaglandins

Center for Experimental Therapeutics, School of Medicine, University of Pennsylvania, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Thrombosis Research (Impact Factor: 2.45). 07/2003; 110(5-6):311-5. DOI: 10.1016/S0049-3848(03)00418-3
Source: PubMed

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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    • "Specific GPCRs have been identified for all the prostanoids, where there are at least nine known prostanoid receptor forms in mouse and man [47, 48]. Although most of the prostaglandin GPCRs are localised at the plasma membrane of platelets, vascular smooth muscle cells, and mast cells, some are situated at the nuclear envelope [49]. Four of these receptor subtypes bind PGE2 (EP1–EP4), two bind PGD2 (DP1 and DP2), and more specific receptors bind PGF2α, PGI2, and TXA2 (FP, IP, and TP, resp.) "
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    ABSTRACT: Omega-6 (n-6) polyunsaturated fatty acids (PUFA) (e.g., arachidonic acid (AA)) and omega-3 (n-3) PUFA (e.g., eicosapentaenoic acid (EPA)) are precursors to potent lipid mediator signalling molecules, termed "eicosanoids," which have important roles in the regulation of inflammation. In general, eicosanoids derived from n-6 PUFA are proinflammatory while eicosanoids derived from n-3 PUFA are anti-inflammatory. Dietary changes over the past few decades in the intake of n-6 and n-3 PUFA show striking increases in the (n-6) to (n-3) ratio (~15 : 1), which are associated with greater metabolism of the n-6 PUFA compared with n-3 PUFA. Coinciding with this increase in the ratio of (n-6) : (n-3) PUFA are increases in chronic inflammatory diseases such as nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, obesity, inflammatory bowel disease (IBD), rheumatoid arthritis, and Alzheimer's disease (AD). By increasing the ratio of (n-3) : (n-6) PUFA in the Western diet, reductions may be achieved in the incidence of these chronic inflammatory diseases.
    Journal of nutrition and metabolism 04/2012; 2012(2):539426. DOI:10.1155/2012/539426
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    • "Considering the central role of adipose tissue in MetS, different adipocyte related genes have been studied as possible candidates in MetS, including peroxisome proliferator-activated receptor-γ (PPARγ), and renin-angiotensin system related genes. PPARγ transcriptionally regulates the expression of genes involved in cell metabolism; endogenous ligands are thought to bind PPARγ and promote downstream gene target transcription [4,5]. From human PPARγ gene two distinct isoforms of mRNA and protein, PPARγ1 and PPARγ2, are spliced [6]. "
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    ABSTRACT: Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.
    Cardiovascular Diabetology 12/2011; 10(1):112. DOI:10.1186/1475-2840-10-112 · 4.02 Impact Factor
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    • "The Tober et al. [4] observations also suggest that EP1 is responsible for a large part of the tumor promoting activity of PGE2. The remainder of the activity is likely due to activation of the other EP receptors or possibly one or more of the peroxisome proliferator-activating receptors, which are known to be activated by eicosanoids [35]. "
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    ABSTRACT: One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE(2). In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE(2) and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE(2) synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.
    CANCER AND METASTASIS REVIEW 12/2011; 30(3-4):465-80. DOI:10.1007/s10555-011-9317-9 · 7.23 Impact Factor
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