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

Elvar Örn Viktorsson; Mari Gabrielsen; Nugalya Kumarachandran; Ingebrigt Sylte; Pål Rongved; Ove Alexander Høgmoen Åstrand; Eili Tranheim Kase

doi:10.1016/j.steroids.2016.12.003

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

Steroids. 2017 Feb:118:119-127. doi: 10.1016/j.steroids.2016.12.003. Epub 2016 Dec 21.

Authors

Elvar Örn Viktorsson¹, Mari Gabrielsen², Nugalya Kumarachandran³, Ingebrigt Sylte², Pål Rongved¹, Ove Alexander Høgmoen Åstrand⁴, Eili Tranheim Kase³

Affiliations

¹ School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
² Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
³ Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
⁴ 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.

PMID: 28011133
DOI: 10.1016/j.steroids.2016.12.003

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.

Keywords: Biological evaluation; Liver X receptors; Molecular modelling; Oxysterols; Steroid synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cholesterol / analogs & derivatives
Cholesterol / chemistry
Cholesterol / metabolism
Hep G2 Cells
Humans
Liver X Receptors / metabolism*
Magnetic Resonance Spectroscopy
Molecular Structure
Oxysterols / metabolism*
Real-Time Polymerase Chain Reaction
Steroids / chemistry
Steroids / metabolism

Substances

Liver X Receptors
Oxysterols
Steroids
22-ketocholesterol
Cholesterol