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

•Fresh waters pollutants target the oxysterol-binding domain of LXRα.•Kinetic and thermodynamic analysis reveals a drug-like potency by these molecules.•These pollutants affect the LXRα-mediated nuclear transcriptional activity. Liver X receptor is a ligand-activated transcription factor, which is m...

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Published in:The Journal of steroid biochemistry and molecular biology 2015-08, Vol.152, p.1-7
Main Authors: Mozzicafreddo, Matteo, Cuccioloni, Massimiliano, Bonfili, Laura, Cecarini, Valentina, Palermo, Francesco Alessandro, Cocci, Paolo, Mosconi, Gilberto, Capone, Aida, Ricci, Irene, Eleuteri, Anna Maria, Angeletti, Mauro
Format: Article
Language:English
Subjects:
Binding Sites
Binding study
Cell culture
Cell Line, Tumor
Environmental Pollutants - metabolism
Environmental Pollutants - pharmacology
Fibric Acids - metabolism
Fibric Acids - pharmacology
Hep G2 Cells
Humans
Liver X receptor
Liver X Receptors
Molecular docking
Molecular Docking Simulation
Organophosphates - metabolism
Organophosphates - pharmacology
Orphan Nuclear Receptors - biosynthesis
Orphan Nuclear Receptors - genetics
Orphan Nuclear Receptors - metabolism
Phthalic Acids - metabolism
Phthalic Acids - pharmacology
Plasticizers
Protein Binding
q-RT-PCR
Receptors, Steroid - metabolism
RNA, Messenger - biosynthesis
Sterol Regulatory Element Binding Protein 1 - biosynthesis
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 1 - metabolism
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Summary:•Fresh waters pollutants target the oxysterol-binding domain of LXRα.•Kinetic and thermodynamic analysis reveals a drug-like potency by these molecules.•These pollutants affect the LXRα-mediated nuclear transcriptional activity. 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 4.3×10−8M. Additionally, non-cytotoxic concentration of these chemicals induced relevant changes in the LXRα gene expression levels and other target genes (SREBP-1c and LGK) in human liver hepatocellular carcinoma cell line (HepG2), as demonstrated by q-RT-PCR.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2015.04.011