title: Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations.
abstract: The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously.
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
authors.forename: Elvar Örn
authors.initials: EÖ
authors.lastname: Viktorsson
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Mari
authors.initials: M
authors.lastname: Gabrielsen
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: Nugalya
authors.initials: N
authors.lastname: Kumarachandran
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Rongved
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway. Electronic address: o.a.h.astrand@farmasi.uio.no.
authors.forename: Ove Alexander Høgmoen
authors.initials: OA
authors.lastname: Åstrand
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: Eili Tranheim
authors.initials: ET
authors.lastname: Kase
mesh_terms: D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D000072376:Oxysterols / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013256:Steroids / Q000737:chemistry / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; D000072376:Oxysterols; D013256:Steroids; C035465:22-ketocholesterol; D002784:Cholesterol
keywords: Biological evaluation; Liver X receptors; Molecular modelling; Oxysterols; Steroid synthesis