Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds: A Potential Application in Alzheimer's Disease?

The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer's Disease (AD). The Asian brown seaweed contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species (, , , , , and ) and the Asian seaweed Sargassum fusiforme using a dual luciferase reporter assay. We analyzed the sterol and fatty acid profiles of the extracts by GC-MS and UPLC MS/MS, respectively, and determined their effects on the expression of LXR and PPAR target genes in several cell lines using quantitative PCR. All extracts were found to activate LXRs, with the extract showing the most pronounced efficacy, comparable to , for LXR activation and transcriptional regulation of LXR-target genes. Extracts of Alaria esculenta, Fucus vesiculosus, and Saccharina latissima showed the highest capacity to activate PPARα, while extracts of , , , and showed the highest capacity to activate PPARγ, comparable to extract. In CCF-STTG1 astrocytoma cells, all extracts induced expression of cholesterol efflux genes (, , and ) and suppressed expression of cholesterol and fatty acid synthesis genes (, , and , and , , and , respectively). Our data show that lipophilic fractions of European brown seaweeds activate LXRs and PPARs and thereby modulate lipid metabolism. These results support the potential of brown seaweeds in the prevention and/or treatment of neurodegenerative diseases and possibly cardiometabolic and inflammatory diseases via concurrent activation of LXRs and PPARs.