Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.

The nuclear receptors-liver X receptors (LXR α and β) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/β activation in luciferase reporter assays and induction of LXR-target genes , and involved in cellular cholesterol turnover in cultured cells: methyl 3β-hydroxychol-5-en-24-oate (), methyl (3β)-3-aldehydeoxychol-5-en-24-oate (), 24-ketocholesterol (), (3β,22E)-3-hydroxycholesta-5,22-dien-24-one () and fucosterol-24,28 epoxide (). These compounds induced but not SREBP1c-mediated lipogenic genes such as , and in HepG2 cells or astrocytoma cells. Moreover, and enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the , encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; and may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.