共查询到20条相似文献,搜索用时 62 毫秒
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The rexinoid LG100754 is a novel RXR:PPARgamma agonist and decreases glucose levels in vivo. 总被引:2,自引:0,他引:2
R M Cesario K Klausing H Razzaghi D Crombie D Rungta R A Heyman D S Lala 《Molecular endocrinology (Baltimore, Md.)》2001,15(8):1360-1369
The RXR serves as a heterodimer partner for the PPARgamma and the dimer is a molecular target for insulin sensitizers such as the thiazolidinediones. Ligands for either receptor can activate PPAR-dependent pathways via PPAR response elements. Unlike PPARgamma agonists, however, RXR agonists like LG100268 are promiscuous and activate multiple RXR heterodimers. Here, we demonstrate that LG100754, a RXR:RXR antagonist and RXR:PPARalpha agonist, also functions as a RXR:PPARgamma agonist. It does not activate other LG100268 responsive heterodimers like RXR:liver X receptoralpha, RXR:liver X receptorbeta, RXR:bile acid receptor/farnesoid X receptor and RXR:nerve growth factor induced gene B. This unique RXR ligand triggers cellular RXR:PPARgamma-dependent pathways including adipocyte differentiation and inhibition of TNFalpha-mediated hypophosphorylation of the insulin receptor, but does not activate key farnesoid X receptor and liver X receptor target genes. Also, LG100754 treatment of db/db animals leads to an improvement in insulin resistance in vivo. Interestingly, activation of RXR:PPARgamma by LG100268 and LG100754 occurs through different mechanisms. Therefore, LG100754 represents a novel class of insulin sensitizers that functions through RXR but exhibits greater heterodimer selectivity compared with LG100268. These results establish an approach to the design of novel RXR-based insulin sensitizers with greater specificity. 相似文献
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p120 acts as a specific coactivator for 9-cis-retinoic acid receptor (RXR) on peroxisome proliferator-activated receptor-gamma/RXR heterodimers. 总被引:1,自引:0,他引:1
T Monden M Kishi T Hosoya T Satoh F E Wondisford A N Hollenberg M Yamada M Mori 《Molecular endocrinology (Baltimore, Md.)》1999,13(10):1695-1703
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Szatmari I Vámosi G Brazda P Balint BL Benko S Széles L Jeney V Ozvegy-Laczka C Szántó A Barta E Balla J Sarkadi B Nagy L 《The Journal of biological chemistry》2006,281(33):23812-23823
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Role of peroxisome proliferator-activated receptor gamma in glucose-induced insulin secretion 总被引:4,自引:0,他引:4
Peroxisome proliferator-activated receptor (PPAR) isoforms (α and γ) are known to beexpressed in pancreatic islets as well as in insulin-producing cell lines.Ligands of PPAR have been shoWn toenhance glucose-induced insulin secretion in rat pancreatic islets.However,their effect on insulin secretionis still unclear.To understand the molecular mechanism by which PPAR7 exerts its effect on glucose-induced insulin secretion,we examined the endogenous activity of PPAR isoforms,and studied the PPARyfunction and its target gene expression in INS-1 cells.We found that:(1)endogenous PPARγ was activatedin a ligand-dependent manner in INS-1 cells;(2)overexpression of PPARy in the absence of PPARγ ligandsenhanced glucose-induced insulin secretion,which indicates that the increased glucose-induced insulin secretionis a PPARγ-mediated event;(3)the addition of both PPARγ and retinoid X receptor (RXR) ligands showed asynergistic effect on the augmentation of reporter activity,suggesting that the hetero-dimerization of PPAR7and RXR is required for the regulation of the target genes;(4)PPARs upregulated both the glucose transporter2 (GLUT2) and Cbl-associated protein (CAP) genes in INS-1 cells.Our findings suggest an importantmechanistic pathway in which PPARγ enhances glucose-induced insulin secretion by activating the expressionof GLUT2 and CAP genes in a ligand-dependent manner. 相似文献
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G.Franck Gbaguidi Luis B Agellon 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2002,1583(2):229-236
Cholesterol 7α-hydroxylase (cyp7a) mediates cholesterol elimination in the liver by catalyzing the first and rate-limiting step in the conversion of cholesterol into bile acids. Peroxisome proliferator-activated receptor α (PPARα; NR1C1) and liver X receptor α (LXRα; NR1H3) are two nuclear receptors that stimulate the murine Cyp7a1 gene. Here we report that co-expression of PPARα and LXRα in hepatoma cells abolishes the stimulation of Cyp7a1 gene promoter in response to their respective agonists. PPARα and LXRα form an atypical heterodimer that binds to two directly adjacent hexameric sequences localized within overlapping PPARα and LXRα response elements (termed Site I), antagonizing the interaction of PPARα:retinoid X receptor α (RXRα) or RXRα:LXRα with the Cyp7a1 gene promoter. Mutations within either hexameric sequences that specifically abolished LXRα:PPARα heterodimer binding to the murine Cyp7a1 Site I also relieved promoter inhibition. The LXRα:PPARα heterodimer may be important in coordinating the expression of genes that encode proteins involved in metabolism of fats and cholesterol. 相似文献
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Albane le Maire Marina Grimaldi Dominique Roecklin Sonia Dagnino Valérie Vivat‐Hannah Patrick Balaguer William Bourguet 《EMBO reports》2009,10(4):367-373
The nuclear receptor retinoid X receptor‐α (RXR‐α)–peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR‐α and PPAR‐γ ligands, the mechanism by which these compounds bind to and activate the RXR‐α–PPAR‐γ heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR–PPAR‐α, ‐γ, ‐δ heterodimers, primarily through its interaction with RXR. In addition, the 1.9 Å resolution structure of the RXR‐α ligand‐binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR‐α ligand‐binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways. 相似文献
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Bai P Houten SM Huber A Schreiber V Watanabe M Kiss B de Murcia G Auwerx J Ménissier-de Murcia J 《The Journal of biological chemistry》2007,282(52):37738-37746
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Eubank DW Duplus E Williams SC Forest C Beale EG 《The Journal of biological chemistry》2001,276(32):30561-30569
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Retinoid X receptor alpha transactivates the hepatitis B virus enhancer 1 element by forming a heterodimeric complex with the peroxisome proliferator-activated receptor. 总被引:3,自引:1,他引:2
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The hepatitis B virus enhancer 1 contains a retinoic acid responsive element (RARE). We have previously demonstrated that retinoid X receptor alpha (RXR alpha) transactivates enhancer 1 by binding to the RARE. The present study has revealed that a heterodimeric complex composed of RXR alpha and peroxisome proliferator-activated receptor (PPAR) interacts with the hepatitis B virus RARE. Transient transfection studies, in conjunction with in vitro DNA binding data, support the hypothesis that the RXR alpha-PPAR heterodimer transactivates enhancer 1. 相似文献
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Discrete roles for peroxisome proliferator-activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators
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Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major role in adipogenesis. PPARgamma binds to DNA as a heterodimer with retinoid X receptor (RXR), and PPARgamma-RXR can be activated by ligands specific for either receptor; the presence of both ligands can result in a cooperative effect on the transactivation of target genes. How these ligands mediate transactivation, however, remains unclear. PPARgamma is known to interact with both the p160/SRC-1 family of coactivators and the distinct, multisubunit coactivator complex called DRIP. A single DRIP subunit, DRIP205 (TRAP220, PBP), binds directly to PPARgamma. Here we report that PPARgamma and RXR selectively interacted with DRIP205 and p160 proteins in a ligand-dependent manner. At physiological concentrations, RXR-specific ligands only induced p160 binding to RXR, and PPARgamma-specific ligands exclusively recruited DRIP205 but not p160 coactivators to PPARgamma. This selectivity was not observed in interaction assays off DNA, implying that the specificity of coactivator binding in response to ligand is strongly influenced by the allosteric effects of DNA-bound heterodimers. These coactivator-selective effects were also observed in transient-transfection assays in the presence of overexpressed p160 or DRIP coactivators. The results suggest that the cooperative effects of PPARgamma- and RXR-specific ligands may occur at the level of selective coactivator recruitment. 相似文献
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