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

ABSTRACT: Liver X receptors (LXR alpha/beta) are nuclear receptors that play a crucial role in regulating various biological processes, including lipid metabolism and inflammation. Activation of these receptors using synthetic pan LXR agonists, such as T0901713 and GW3965 has demonstrated neuroprotective effects, making them promising therapeutic targets for neurodegenerative disorders like Alzheimer’s Disease (AD). However, the clinical applications of synthetic pan-LXR agonists are limited by adverse hepatic effects including hypertriglyceridemia and steatosis. Thus, dissociating the beneficial effects of LXR agonism from the deleterious side effects in the liver will be required for the development of LXR agonists as better potential therapeutics. In this study, we investigated 24(S)-saringosterol, a phytosterol derived from the seaweed Sargassum fusiforme, which has previously been reported to exhibit LXR agonist activity without inducing hepatic steatosis. To elucidate its effects on lipid metabolism and inflammatory pathways, we used two distinct cell lineages-myeloid and hepatic cells. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE315287 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:GLUCOCORTICOIDS are steroid hormones that strongly influence intermediary carbohydrate metabolism by increasing the transcription rate of glucose-6-phosphatase (G6Pase) a key enzyme of gluconeogenesis, and suppress the immune system which makes them one of the most important therapeutic agents in the treatment of allergic, autoimmune and inflammatory diseases. The biologic actions of circulating glucocorticoids are transmitted to the cells nucleus by the glucocorticoid receptor (GR). The nuclear liver X receptors (LXRs) bind to cholesterol metabolites, heterodimerize with the retinoid X receptor (RXR), and regulate the cholesterol turnover, the hepatic glucose metabolism by decreasing the expression of G6Pase, and repress a set of inflammatory genes in immune cells. The aim of this study is to evaluate the crosstalk between the GR- and LXR-mediated signaling systems. Transient transfection-based reporter assays and gene silencing methods using siRNAs for LXRs showed that overexpression/ligand (GW3965) activation of LXRs/RXRs repressed GR-stimulated transactivation of certain glucocorticoid response element (GRE)-driven promoters in a gene-specific fashion. Activation of LXRs by GW3965 attenuated dexamethasone-stimulated elevation of circulating glucose in rats and suppressed dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase (G6Pase) in rats, mice and human hepatoma HepG2 cells. In microarray transcriptomic analysis of rat liver, GW3965 differentially regulated glucocorticoid-induced transcriptional activity of about 15% of endogenous glucocorticoid-responsive genes. Mechanistically, and in vitro chromatin immunoprecipitation assay, we found that LXRα/RXRα bound GREs and inhibited GR binding to these DNA sequences in a gene-specific fashion. These novel results were further confirmed in in vivo binding assays, and in gel mobility shift assays, where recombinant LXRα/RXRα proteins were used to examine their interaction with classic or G6Pase GREs. We propose that administration of LXR agonists may be beneficial in glucocorticoid treatment- or stress-associated dysmetabolic states by directly attenuating the transcriptional activity of the GR on glucose and/or lipid metabolism.

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

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