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

Abstract

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 Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme 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 (Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) 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 Himanthalia elongata extract showing the most pronounced efficacy, comparable to Sargassum fusiforme, 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 Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPARγ, comparable to Sargassum fusiforme extract. In CCF-STTG1 astrocytoma cells, all extracts induced expression of cholesterol efflux genes (ABCG1, ABCA1, and APOE) and suppressed expression of cholesterol and fatty acid synthesis genes (DHCR7, DHCR24, HMGCR and SREBF2, and SREBF1, ACACA, SCD1 and FASN, 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.

Supplementation of Seaweed Extracts to the Diet Reduces Symptoms of Alzheimer’s Disease in the APPswePS1ΔE9 Mouse Model

“…Because the cellular cholesterol content may affect the cytokine production of macrophages, we determined the effect of the extracts of H. elongata and S. fusiforme on cholesterol efflux in THP-1-derived macrophages [ 15 ]. In line with our previous findings that H. elongata and S. fusiforme extracts upregulate the expression of genes involved in cholesterol efflux [ 28 ], the H. elongata lipid extract and S. fusiforme SCF extract promoted the efflux of cholesterol from THP-1-derived macrophages. The H. elongata extract promoted the cholesterol efflux to ApoA-I and, to a lesser extent, to HDL, but only at a saringosterol concentration of 2.5 µM ( Figure 8 a,b).…”

“…We first tested whether S. fusiforme SCF extract activated LXRs, as previously demonstrated with the chloroform–methanol extracts of S. fusiforme and H. elongata [ 25 , 28 ], using a cell-based dual luciferase reporter assay. The data demonstrated that the S. fusiforme SCF extract activated both LXRα and LXRβ in HEK293, CCF-STTG1, SH-SY5Y, and CHME3 cells ( Figure 1 ).…”

“…Lipids of H. elongata and S. fusiforme were extracted using the Folch method as described previously [ 28 ]. Dried H. elongata (The Seaweed Company, Schiedam, The Netherlands) and S. fusiforme (TerraSana B.V., Leimuiden, The Netherlands) were finely powdered and soaked overnight in a chloroform–methanol (2:1) mixture at room temperature and, then, exposed to Ultraviolet-C light (wavelengths: 200–280 nm).…”

“…Here, we assess the effects of an extract of S. fusiforme obtained by supercritical fluid (SCF) extraction, which contains bioactive molecules but is free from iAs, as well as a lipid extract of the European brown seaweed Himanthalia elongata ( H. elongata ) on cognition and AD-related pathology in a mouse model for AD. Recently, we demonstrated that the H. elongata lipid extract, containing concentrations of 24( S )-saringosterol comparable to S. fusiforme , activates LXRs [ 28 ]. Our data demonstrated the potential of H. elongata extracts in the prevention of cognitive decline in APPswePS1ΔE9 mice.…”

From Dietary Cholesterol to Blood Cholesterol

“…A disturbed brain C metabolism is associated with Alzheimer’s disease (AD) and stimulation of cholesterol turnover in the brain was found to ameliorate the development of cognitive decline in AD mice. Martens et al [ 20 ] described the upregulation of C efflux genes and downregulation of lipogenesis genes by incubation with lipophilic extracts of six European brown seaweed species. Their results confirm the described prevention of disease progression in AD mice by the Asian brown seaweed species Sargassum fusiforme [ 21 ].…”