TY - JOUR
T1 - Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds
T2 - A Potential Application in Alzheimer's Disease?
AU - Martens, Nikita
AU - Zhan, Na
AU - Voortman, Gardi
AU - Leijten, Frank P. J.
AU - van Rheenen, Connor
AU - van Leerdam, Suzanne
AU - Geng, Xicheng
AU - Huybrechts, Michiel
AU - Liu, Hongbing
AU - Jonker, Johan W. W.
AU - Kuipers, Folkert
AU - Lutjohann, Dieter
AU - Vanmierlo, Tim
AU - Mulder, Monique T. T.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - The nuclear liver X receptors (LXR & alpha;/& beta;) and peroxisome proliferator-activated receptors (PPAR & alpha;/& gamma;) 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 LXR & alpha;/& beta;- and PPAR & alpha;/& gamma;-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 PPAR & alpha;, while extracts of Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPAR & gamma;, 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.
AB - The nuclear liver X receptors (LXR & alpha;/& beta;) and peroxisome proliferator-activated receptors (PPAR & alpha;/& gamma;) 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 LXR & alpha;/& beta;- and PPAR & alpha;/& gamma;-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 PPAR & alpha;, while extracts of Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPAR & gamma;, 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.
KW - nuclear receptor superfamily
KW - liver X receptors
KW - peroxisome proliferator-activated receptors
KW - lipid metabolism
KW - phytosterols
KW - seaweed
KW - Alzheimer's Disease
KW - AMYLOID PRECURSOR PROTEIN
KW - FATTY-ACIDS
KW - GENE-EXPRESSION
KW - PPAR-GAMMA
KW - MOUSE MODEL
KW - IN-VITRO
KW - SYNAPTIC PLASTICITY
KW - MEMORY IMPAIRMENT
KW - ELEMENT-BINDING
KW - ROSIGLITAZONE
U2 - 10.3390/nu15133004
DO - 10.3390/nu15133004
M3 - Article
C2 - 37447330
SN - 2072-6643
VL - 15
JO - Nutrients
JF - Nutrients
IS - 13
M1 - 3004
ER -