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Liver X Receptor (liver + x_receptor)
Selected AbstractsLiver X receptor is a therapeutic target in collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 4 2007Subba R. Chintalacharuvu PhD No abstract is available for this article. [source] Liver X receptor agonism promotes articular inflammation in murine collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Darren L. Asquith Objective Liver X receptors (LXRs) have previously been implicated in the regulation of inflammation and have, in general, been ascribed an antiinflammatory role. This study was therefore undertaken to explore the biologic mechanisms of LXRs in vivo and in vitro in an experimental inflammatory arthritis model. Methods Male DBA/1 mice were immunized with type II collagen and treated from an early or established stage of arthritis with 2 different concentrations of the LXR agonists T1317 and GW3965 or vehicle control. The mice were monitored for articular inflammation and cartilage degradation by scoring for clinical signs of arthritis, histologic examination of the joints, and analysis of serum cytokine and antibody levels. In vitro, primary human monocytes and T cells were cultured in the presence of GW3965 or T1317, and the concentrations of proinflammatory cytokines were measured by multiplex assay. Results Contrary to expectations, LXR agonism with the use of 2 discrete, specific molecular entities led to substantial exacerbation of articular inflammation and cartilage destruction in this murine collagen-induced arthritis model. This was associated ex vivo with elevated cytokine expression, with enhanced Th1 and Th17 cellular responses, and with elevated collagen-specific autoantibody production. In vitro, LXR agonists, in concert with lipopolysaccharide, promoted cytokine and chemokine release from human monocytes, and similar effects were observed in a T cell,macrophage coculture model that closely recapitulates the pathways that drive synovial cytokine release. Conclusion Since LXRs are present in rheumatoid arthritis (RA) synovium, these results suggest that LXR-mediated pathways could exacerbate the chronic inflammatory response typical of RA. [source] The G protein,coupled receptor G2A: Involvement in hepatic lipid metabolism and gallstone formation in mice,HEPATOLOGY, Issue 4 2008Laura E. Johnson The G2A receptor is a member of the ovarian cancer G protein,coupled receptor 1 family of stress-inducible G protein,coupled receptors. In this study, we examined the hepatobiliary effects of loss of function of G2A in mice fed either a chow or lithogenic diet. G2A-deficient (G2A,/,) mice fed chow had a 25% reduction in biliary phosphatidylcholine content, reduced hepatic gene expression of the phosphatidylcholine transporter adenosine triphosphate,binding cassette B4, and an 8-fold increase in expression of the nuclear receptor liver X receptor (LXR). Despite the increased expression of LXR, transcription of several LXR target genes was reduced. G2A,/, mice fed a lithogenic diet had rapid gallstone formation, an increased cholesterol saturation index, a 2.5-fold increase in farnesoid X receptor expression, a 5-fold increase in LXR expression, and a 90% reduction in cholesterol 7,-hydroxylase expression in comparison with wild-type mice. There were no changes in gallbladder volume. Conclusion: These data demonstrate that the G2A receptor is important for hepatobiliary bile salt, cholesterol, and phospholipid homeostasis and for the pathogenesis of cholesterol gallstone formation. (HEPATOLOGY 2008;48:1138,1148.) [source] Nuclear receptors and drug disposition gene regulationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2005Rommel G. Tirona Abstract In this minireview, the role of various nuclear receptors and transcription factors in the expression of drug disposition genes is summarized. Specifically, the molecular aspects and functional impact of the aryl hydrocarbon receptor (AhR), nuclear factor-E2 p45-related factor 2 (Nrf2), hepatocyte nuclear factor 1, (HNF1,), constitutive androstane receptor (LAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor , (PPAR,), hepatocyte nuclear factor 4, (HNF4,), vitamin D receptor (VDR), liver receptor homolog 1 (LRH1), liver X receptor (LXR,), small heterodimer partner-1 (SHP-1), and glucocorticoid receptor (GR) on gene expression are detailed. Finally, we discuss some current topics and themes in nuclear receptor-mediated regulation of drug metabolizing enzymes and drug transporters. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1169,1186, 2005 [source] Probing Small-Molecule Binding to the Liver-X Receptor: A Mixed-Model QSAR StudyMOLECULAR INFORMATICS, Issue 1-2 2010Morena Spreafico Abstract The LXR model has been added in the VirtualToxLab, a fully automated technology that allows for the identification of the endocrine-disrupting potential of drugs, chemicals and natural products. This protocol has then been applied to screen a series of 161 natural compounds probing their binding to the LXR. The results of the simulation were compared with experimental data (where available) and suggest that the LXR model can be applied to predict the binding affinity of existing or hypothetical compounds for screening purposes. The binding of 52 ligands towards the liver X receptors (LXRs) was identified trough docking to the three-dimensional protein structure and quantified by multidimensional QSAR (mQSAR), an approach referred to as ,mixed-model QSAR'. The model was validated by the prediction of 17 external compounds (oxysterols) present neither in the training nor in the test set. The robustness of the model was verified by consensus scoring using a conceptually different methodology, and chance correlation was ruled out by a series of scramble tests. [source] | |||||||||||||