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Receptor-interacting protein 140 (RIP140) contains multiple receptor interaction domains and interacts with retinoic acid receptors in a ligand-dependent manner. Nine LXXLL receptor-interacting motifs are organized into two clusters within this molecule, each differentially interacting with retinoic acid receptor (RAR) and retinoid X receptor (RXR). RAR interacts with the 5' cluster, whereas RXR interacts with both clusters. Additionally, a third ligand-dependent receptor-interacting domain is assigned to the very C terminus of this molecule, which contains no LXXLL motif. In mammalian cells, receptor heterodimerization is required for efficient interaction of RAR/RXR with RIP140. Furthermore, the heterodimeric, holoreceptors cooperatively interact with RIP140, which requires the activation function 2 domains of both receptors. By using different retinoic acid reporter systems, it is demonstrated that RIP140 strongly suppresses retinoic acid induction of reporter activities, but coactivator SRC-1 enhances it. Furthermore, an intrinsic repressive activity of RIP140 is demonstrated in a GAL4 fusion system. Unlike receptor corepressor, which interacts with antagonist-bound RAR/RXRs, RIP140 does not interact with antagonist-occupied RAR/RXR dimers. These data suggest that RIP140 represents a third coregulator category that is able to suppress the activation of certain agonist-bound hormone receptors.  相似文献   

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Little is known about the mechanisms responsible for the fall in fatty acid oxidation during the development of cardiac hypertrophy. We focused on the effects of nuclear factor (NF)-kappaB activation during cardiac hypertrophy on the activity of peroxisome proliferator-activated receptor (PPAR) beta/delta, which is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. Phenylephrine-induced cardiac hypertrophy in neonatal rat cardiomyocytes caused a reduction in the expression of pyruvate dehydrogenase kinase 4 (Pdk4), a target gene of PPARbeta/delta involved in fatty acid utilization, and a fall in palmitate oxidation that was reversed by NF-kappaB inhibitors. Lipopolysaccharide stimulation of NF-kappaB in embryonic rat heart-derived H9c2 myotubes, which only express PPARbeta/delta, caused both a reduction in Pdk4 expression and DNA binding activity of PPARbeta/delta to its response element, effects that were reversed by NF-kappaB inhibitors. Coimmunoprecipitation studies demonstrated that lipopolysaccharide strongly stimulated the physical interaction between the p65 subunit of NF-kappaB and PPARbeta/delta, providing an explanation for the reduced activity of PPARbeta/delta. Finally, we assessed whether this mechanism was present in vivo in pressure overload-induced cardiac hypertrophy. In hypertrophied hearts of banded rats the reduction in the expression of Pdk4 was accompanied by activation of NF-kappaB and enhanced interaction between p65 and PPARbeta/delta. These results indicate that NF-kappaB activation during cardiac hypertrophy down-regulates PPARbeta/delta activity, leading to a fall in fatty acid oxidation, through a mechanism that involves enhanced protein-protein interaction between the p65 subunit of NF-kappaB and PPARbeta/delta.  相似文献   

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Although abnormalities in cardiac fatty acid metabolism are involved in the development of several cardiac pathologies, the mechanisms underlying these changes are not well understood. Given the prominent role played by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta in cardiac fatty acid metabolism, the aim of this study was to examine the effects of nuclear factor (NF)-kappaB activation on the activity of this nuclear receptor. Embryonic rat heart-derived H9c2 cells stimulated with lipopolysaccharide (LPS) showed a reduction (38%, P<0.05) in the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK4) that was prevented in the presence of the NF-kappaB inhibitors parthenolide (10 microM) and atorvastatin (10 microM). Electrophoretic mobility shift assay revealed that both parthenolide and atorvastatin significantly decreased LPS-stimulated NF-kappaB binding activity in H9c2 cardiac cells. LPS-stimulation of H9c2 cardiac cells also led to a 30% reduction (P<0.05) in the mRNA levels of PPARgamma Coactivator 1 (PGC-1) that was consistent with the reduction in the protein levels of this coactivator. In the presence of either atorvastatin or parthenolide, the reduction in PGC-1 expression was prevented. Co-immunoprecipitation studies showed that LPS-stimulation led to a reduction in the physical interaction between PGC-1 and PPARbeta/delta and that this reduction was prevented in the presence of atorvastatin. Finally, electrophoretic mobility shift assay revealed that parthenolide and atorvastatin prevented LPS-mediated reduction in PPARbeta/delta binding activity in H9c2 cardiac cells. These results suggest that LPS-mediated NF-kappaB activation inhibits the expression of genes involved in fatty acid metabolism by a mechanism involving reduced expression of PGC-1, which in turn affects the PPARbeta/delta transactivation of target genes involved in cardiac fatty acid oxidation.  相似文献   

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Mutation of the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARbeta/delta-null mutant embryos. While very little is known at present about the pathway governed by PPARbeta/delta in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPARbeta/delta-null embryos is found in the giant cell layer. PPARbeta/delta activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPARbeta/delta is silenced. Conversely, exposure of Rcho-1 cells to a PPARbeta/delta agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPARbeta/delta activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPARbeta/delta also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPARbeta/delta-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARbeta/delta in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARbeta/delta agonist as therapeutic agents of broad application.  相似文献   

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The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood, but there is a strong correlation between insulin resistance and intramyocellular lipid accumulation in skeletal muscle. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. The aim of this work was to study whether the exposure of skeletal muscle cells to palmitate affected peroxisome proliferator-activated receptor (PPAR) beta/delta activity. Here, we report that exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate reduced (74%, P<0.01) the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK-4), which is involved in fatty acid utilization. This reduction was not observed in the presence of the PPARbeta/delta agonist L-165041. This drug prevented palmitate-induced nuclear factor (NF)-kappaB activation. Increased NF-kappaB activity after palmitate exposure was associated with enhanced protein-protein interaction between PPARbeta/delta and p65. Interestingly, treatment with the PPARbeta/delta agonist L-165041 completely abolished this interaction. These results indicate that palmitate may reduce fatty acid utilization in skeletal muscle cells by reducing PPARbeta/delta signaling through increased NF-kappaB activity.  相似文献   

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Monoclonal antibodies that recognize the human, mouse, and rat retinoic acid receptor alpha (RAR alpha) protein have been generated using synthetic peptides. Less well-characterized monoclonal antibodies were also generated against the RAR beta and RAR gamma proteins. Monoclonal antibodies of the IgG1 (R alpha 10) and IgG2a (R alpha 13) isotypes effectively and specifically recognize both the human and mouse RAR alpha protein. Preincubation of the antibodies with the synthetic RAR alpha peptide, but not with the RAR beta or RAR gamma peptides, blocked recognition of the approximately 55 kDa RAR alpha protein on western blots. These monoclonal antibodies also detected differing levels of RAR alpha in various rat tissues. These monoclonal antibodies will serve as powerful reagents to study the structure and regulation of the retinoic acid receptor protein.  相似文献   

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