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 alpha and beta) 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 Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXR alpha/beta activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3 beta-hydroxychol-5-en-24-oate (S1), methyl (3 beta)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3 beta,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 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. This research was supported by the National Natural Science Foundation of China (grant numbers: 81973433), Shandong Provincial Natural Science Foundation of China (grant numbers: ZR2018MH041), Alzheimer Nederland (grant numbers: WE.03-2018-06 AN), and NWO-TTW (grant numbers: #16437). The authors gratefully acknowledge the financial support from China Scholarship Council (File No. 201906330056).