53 research outputs found
Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis
Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite
FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver
diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury
caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from
the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated
genes and biological functions.
Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation
assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of
human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and
thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic
FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to
investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model
of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by
assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in
bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a
basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed
to rescue from liver injury and downregulated the expression of MRP4.
Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible
strategy to target obstructive cholestasis
International union of basic and clinical pharmacology. XC. multisite pharmacology:Recommendations for the nomenclature of receptor allosterism and allosteric ligands
Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties
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