The phytosterol 24 (S)-saringosterol alters lipid homeostasis and inflammatory pathways in a cell-specific manner.

Our results demonstrate that 24(S)-saringosterol exhibits a stronger activation of LXR regulated gene expressions leading to dose-dependent upregulation of the cholesterol efflux transporter ABCA1 in both cell types. In myeloid cells, including microglia and bone marrow-derived macrophages, like GW3965, 24(S)-saringosterol exhibited anti-inflammatory effects by downregulating genes involved in interferon- pathways and promoted cholesterol efflux by upregulating ABCA1 via LXR activation.

In myeloid as well as hepatic cells, 24(S)-saringosterol reduced the expression of cholesterol biosynthesis genes as well as LDLR via SREBP2, in contrast to GW3965, which upregulated expression of lipid synthesis genes via SREBP1. These findings highlight the therapeutic potential of 24(S)-saringosterol as a dissociated LXR agonist that effectively mitigates the adverse effects associated with synthetic LXR agonists. This compound represents a promising candidate for further investigation in the context of AD and other metabolic and inflammatory disorders.