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Farnesoid X Receptor (farnesoid + x_receptor)
Selected AbstractsChemInform Abstract: Pyrrole[2,3-d]azepino Compounds as Agonists of the Farnesoid X Receptor (FXR).CHEMINFORM, Issue 5 2010John F. Mehlmann Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: Hype or hope?HEPATOLOGY, Issue 1 2004Michael Trauner M.D. Farnesoid X receptor (FXR) is a bile acid,activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease. [source] Functional analysis of the rat bile salt export pump gene promoterFEBS JOURNAL, Issue 14 2002Regulation by bile acids, drugs, endogenous compounds The 5, flanking region of the bile salt export pump (Bsep) gene was systematically analysed to provide the basis for understanding the mechanisms which regulate Bsep transcription. In addition substrates and drugs were investigated for their ability to alter Bsep promoter activity. Bsep promoter function was restricted to hepatocyte derived HepG2 cells. The 5, deletional analysis revealed a biphasic shape of reporter gene activities, indicating a suppressive element between nucleotides ,800 and ,512. Two consensus sites for the farnesoid X receptor (FXR) were located at nucleotides ,473 and ,64. The latter was characterized as functionally active in bile acid-mediated feed-back regulation of Bsep transcription. Bsep promoter activity was reduced by rifampin and ,-estradiol. The anti-estrogen tamoxifen stimulated promoter activity. Dexamethasone, hydrocortisone and phenobarbital had no effect on Bsep promoter activity. In conclusion, the data suggest that transcriptional regulation of the Bsep gene can be modulated by a number of endogenous compounds and xenobiotics. FXR was a major regulatory factor, mediating bile acid feed-back stimulation of Bsep transcription. [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] Expression and regulation of the bile acid transporter, OST, -OST, in rat and human intestine and liverBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2009Ansar A. Khan Abstract The regulation of the OST, and OST, expression was studied in the rat jejunum, ileum, colon and liver and in human ileum and liver by ligands for the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR) and glucocorticoid receptor (GR) using precision cut tissue slices. The gradient of protein and mRNA expression in segments of the intestine for rOST, and rOST, paralleled that of rASBT. OST, and OST, mRNA expression, quantified by qRT-PCR, in rat jejunum, ileum, colon and liver, and in human ileum and liver was positively regulated by FXR and GR ligands. In contrast, the VDR ligand, 1,25(OH)2D3 decreased the expression of rOST, -rOST, in rat intestine, but had no effect on human ileum, and rat and human liver slices. Lithocholic acid (LCA) decreased the expression of rOST, and rOST, in rat ileum but induced OST, -OST, expression in rat liver slices, and human ileum and liver slices. The PXR ligand, pregnenolone-16, carbonitrile (PCN) had no effect. This study suggest that, apart from FXR ligands, the OST, and OST, genes are also regulated by VDR and GR ligands and not by PXR ligands. This study show that VDR ligands exerted different effects on OST, -OST, in the rat and human intestine and liver compared with other nuclear receptors, FXR, PXR, and GR, pointing to species- and organ-specific differences in the regulation of OST, -OST, genes. Copyright © 2009 John Wiley & Sons, Ltd. [source] Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver diseaseJOURNAL OF DIGESTIVE DISEASES, Issue 2 2009Jue WEI Nonalcoholic fatty liver disease is characterized by an accumulation of excess triglycerides in hepatocytes, and insulin resistance is now considered the fundamental operative mechanism throughout the prevalence and progression of the disease. Besides their role in dietary lipid absorption and cholesterol homeostasis, evidence has accumulated that bile acids are also signaling molecules that play two important roles in glucose and lipid metabolism: in the nuclear hormone receptors as farnesoid X receptors (FXR), as well as ligands for G-protein-coupled receptors TGR5. The activated FXR-SHP pathway regulates the enterohepatic recycling and biosynthesis of bile acids and underlies the down-regulation of hepatic fatty acid and triglyceride biosynthesis and very low density lipoprotein production mediated by sterol-regulatory element-binding protein-1c. The bile acid-TGR5-cAMP-D2 signaling pathway in human skeletal muscle in the fasting,feeding cycle increases energy expenditure and prevents obesity. Therefore, a molecular basis has been provided for a link between bile acids, lipid metabolism and glucose homeostasis, which can open novel pharmacological approaches against insulin resistance and nonalcoholic fatty liver disease. [source] | |||||||||||||