Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations

[Display omitted] •New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A...

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Bibliographic Details
Published in:Steroids 2017-02, Vol.118, p.119-127
Main Authors: Viktorsson, Elvar Örn, Gabrielsen, Mari, Kumarachandran, Nugalya, Sylte, Ingebrigt, Rongved, Pål, Åstrand, Ove Alexander Høgmoen, Kase, Eili Tranheim
Format: Article
Language:English
Subjects:
Biological evaluation
Cholesterol - analogs & derivatives
Cholesterol - chemistry
Cholesterol - metabolism
Hep G2 Cells
Humans
Liver X receptors
Liver X Receptors - metabolism
Magnetic Resonance Spectroscopy
Molecular modelling
Molecular Structure
Oxysterols
Oxysterols - metabolism
Real-Time Polymerase Chain Reaction
Steroid synthesis
Steroids - chemistry
Steroids - metabolism
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Summary:[Display omitted] •New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A new oxysterol analog was found to reduce lipogenesis. 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.
ISSN:0039-128X
1878-5867
DOI:10.1016/j.steroids.2016.12.003