Environmental pollutants directly affect the liver X receptor alpha activity: Kinetic and thermodynamic characterization of binding

Publication date: Available online 11 April 2015 Source:The Journal of Steroid Biochemistry and Molecular Biology Author(s): Matteo Mozzicafreddo , Massimiliano Cuccioloni , Laura Bonfili , Valentina Cecarini , Francesco Alessandro Palermo , Paolo Cocci , Gilberto Mosconi , Aida Capone , Irene Ricci , Anna Maria Eleuteri , Mauro Angeletti Liver X receptor is a ligand-activated transcription factor, which is mainly involved in cholesterol homeostasis, bile acid and triglycerides metabolism, and, as recently discovered, in the glucose metabolism by direct regulation of liver glucokinase. Its modulation by exogenous factors, such as drugs, industrial by-products, and chemicals is documented. Owing to the abundance of these synthetic molecules in the environment, and to the established target role of this receptor, a number of representative compounds of phthalate, organophosphate and fibrate classes were tested as ligands/modulators of human liver X receptor, using an integrated approach, combining an in silico molecular docking technique with an optical SPR biosensor binding study. The compounds of interest were predicted and proved to target the oxysterols-binding site of human LXRα with measurable binding kinetic constants and with affinities ranging between 4.3×10−7 and 4.3×10−8 M. Additionally, non-cytotoxic concentration of these chemicals induced relevant changes in the LXRα gene expression levels and other target genes (SREBP-1c and ...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research

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