PPARS

A GRID/CPCA analysis of the three subtypes of Peroxisome Proliferator-Activated Receptors (PPARs) vas reported by Pirard [18] using three PPARa, eight PPARy, and three PPARd X-ray structures of the ligand binding domain (LED). 

The CPCA supenveight plot sho ved that hydrophobic and steric interactions contribute mostly to the discrimination bet veen the three PPAR subtypes. From the supenveight plot, the authors selected three representative probes (DRY, C3 and OH) for the subsequent analysis. 

Due to the position of the subtypes in the score plot, the pseudofield contours in PC 1 distinguished PPARy from PPARd, ivhereas PC 2 highlighted the differences betv een PPARa and PPARy/d. Interestingly, all PPARy LEDs crystallized ivith an agonist occupied the same region in the score plot, -while the apo form and the one with a partial agonist were very close to the PPARa LEDs. 

Although the three remaining subsites of the PPAR LED exhibited less variation than the distal pockets, the CRID/CPCA calculations revealed some scope for selective interactions, in particular with the OH and C3 probes within the linker and head regions. This analysis agreed well with site-directed mutagenesis experiments, as well as the selectivity of known inhibitors. 

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Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

Workers at Lilly prepared the oxazole-containing, dual PPAR ot/y agonist 23, through Robinson-Gabriel cyclodehydration of ketone 22 with acetic anhydride and sulfuric acid in refluxing ethyl acetate. ... 

P-selectin, VEGFR2, VCAM, pPAR, CD55, Eotaxin-3, MCP-1... 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

Diabetes Mellitus Insulin Receptor Glucose Transporters ATP-dependent K+Channel PPARs... 

Current evidence suggests that PPAR activation may limit inflammation and hence atherosclerosis. Both PPAR-a and PPAR-y can reduce T-cell activation, as shown by decreased production of EFN-y. PPAR-a agonists also rqness endothelial VCAM-1 expression and inhibit the inflammatory activation of vascular SMCs, while PPAR-y agonists repress endothelial chemokine expression and decrease macrophage MMP production. 

In humans, biomarker responses to PPAR agonists by and large support possible antiatherosclerotic benefits, although recent clinical trial results have not proven conclusive. Further large-scale trials should help define the role of PPAR agonist therapy on cardiovascular events in at-risk populations. 

HMG-CoA-Reductase-Inhibitors Peroxisome Proliferator-Activated Recqrtors (PPARs) ACE Inhibitors Antiplatelet Drugs... 

Brown J, Plutzky J (2007) PPARs as transcriptional nodal points and therapeutic targets. Circulation 115 518-533... 

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

Peroxisome Proliferator-Activated Receptor (PPARs) HMG-CoA Reductase Inhibitors... 

Peroxisome Proliferator-Activated Receptors (PPARs) Diabetes Mellitus... 

PPAR Xenochemical Induction of CYP4A Enzymes and Role in Rodent Hepatocarcinogenesis... 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Peraza MA, Burdick AD, Marin HE et al (2006) The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 90 269-295... 

PPARs PPARa NR1C1 PPAR8 NR1C2, PPAR 3, NUC1, FAAR (fatty acid-activated receptor) PPARy NR1C3... 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

Peroxisome Proliferator-Activated Receptors. Figure 2 Binding of PPAR RXR heterodimers to DR1 PPRE-responsive elements. Abbreviations DR1, a direct repeat organization of the A/GGGTCA hexamer half-site separated by a single nucleotide spacer. 

Figure 3 provides a very general overview of transcriptional activation in response to a PPAR ligand. Fig. 3a shows the schematic representation of a PPAR target gene in the absence of PPAR ligand. Co-repressor proteins bound to both unliganded PPAR and RXR... 

Peroxisome Proliferator-Activated Receptors. Figure 3 Transcription of PPAR target genes. A schematic representation of the transcription of PPAR-regulated genes in the absence (a) and presence (b) of PPAR ligand. Abbreviations PPAR-RE, peroxisome proliferator-activated receptor-response element RNA Pol II, RNA polymerase II TATA-BP, TATA-binding protein. 

The tissue-specific patterns of expression of the PPAR. isotypes suggested that these proteins have distinct physiological roles, and this was further supported when each was specifically disrupted in mouse gene knockout models. 

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

The expression of all three PPAR isotypes peaks in the rat central nervous system between days 13.5-18.5 of gestation, and while expression of both PPARa and PPARy decline post-natally, expression of PPARS remains high (except for the retina, where all three isoforms are expressed in the adult rodent). An important role for PPARS in CNS development is underscored by the occurrence of defective myelination in the PPARS-null mouse. 

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