title: Environmental pollutants directly affect the liver X receptor alpha activity: Kinetic and thermodynamic characterization of binding.
abstract: 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 LGK) in human liver hepatocellular carcinoma cell line (HepG2), as demonstrated by q-RT-PCR.
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy. Electronic address: matteo.mozzicafreddo@unicam.it.
authors: Matteo
authors: M
authors: Mozzicafreddo
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Massimiliano
authors: M
authors: Cuccioloni
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Laura
authors: L
authors: Bonfili
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Valentina
authors: V
authors: Cecarini
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Francesco Alessandro
authors: FA
authors: Palermo
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Paolo
authors: P
authors: Cocci
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Gilberto
authors: G
authors: Mosconi
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Aida
authors: A
authors: Capone
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Irene
authors: I
authors: Ricci
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Anna Maria
authors: AM
authors: Eleuteri
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032 Italy.
authors: Mauro
authors: M
authors: Angeletti
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004785:Environmental Pollutants / Q000378:metabolism* / Q000494:pharmacology; D058607:Fibric Acids / Q000378:metabolism* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000378:metabolism* / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010795:Phthalic Acids / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D004785:Environmental Pollutants; D058607:Fibric Acids; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D010755:Organophosphates; D057093:Orphan Nuclear Receptors; D010795:Phthalic Acids; D012333:RNA, Messenger; D011987:Receptors, Steroid; D051780:Sterol Regulatory Element Binding Protein 1; D000098825:Oxysterol Binding Proteins; C032279:phthalic acid
keywords: Binding study; Cell culture; Liver X receptor; Molecular docking; Plasticizers; q-RT-PCR