title: Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist.
abstract: The liver X receptors (LXRalpha and LXRbeta) are transcription factors that control the expression of genes primarily involved in cholesterol metabolism. In the brain, in addition to normal neuronal function, cholesterol metabolism is important for APP proteolytic cleavage, secretase activities, Abeta aggregation and clearance. Particularly significant in this respect is LXR mediated transcriptional control of APOE, which is the only proven risk factor for late onset Alzheimer's disease. Using a transactivation reporter assay for screening pharmacologically active compounds and off patent drugs we identified the proton pump inhibitor Lansoprazole as an LXR agonist. In secondary screens and counter-screening assays, it was confirmed that Lansoprazole directly activates LXR, increases the expression of LXR target genes in brain-derived human cell lines, and increases Abca1 and Apo-E protein levels in primary astrocytes derived from wild type but not LXRalpha/beta double knockout mice. Other PPIs activate LXR as well, but the efficiency of activation depends on their structural similarities to Lansoprazole. The identification of a widely used drug with LXR agonist-like activity opens the possibility for systematic preclinical testing in at least two diseases--Alzheimer's disease and atherosclerosis.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Cronican
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Fitz
authors.forename: Tam
authors.initials: T
authors.lastname: Pham
authors.forename: Allison
authors.initials: A
authors.lastname: Fogg
authors.forename: Brionna
authors.initials: B
authors.lastname: Kifer
authors.forename: Radosveta
authors.initials: R
authors.lastname: Koldamova
authors.forename: Iliya
authors.initials: I
authors.lastname: Lefterov
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D064747:Lansoprazole; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009457:Neuroglia / Q000378:metabolism; D009853:Omeprazole / Q000737:chemistry / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D009853:Omeprazole