Department of Internal Medicine, Section Pharmacology and Vascular Medicine, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
Department of Neuroscience, Biomedical Research Institute, European Graduate School of Neuroscience, Hasselt University, B-3590 Hasselt, Belgium.
Nutrients. 2023 Jun 30;15(13):3004. doi: 10.3390/nu15133004.
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.
核受体肝 X 受体 (LXRα/β) 和过氧化物酶体增殖物激活受体 (PPARα/γ) 参与多种生物过程的调节，包括脂质代谢和炎症。这些受体的激活已被发现具有神经保护作用，使其成为阿尔茨海默病 (AD) 等神经退行性疾病的有趣治疗靶点。亚洲褐藻含有 LXR 激活 (氧) 植物甾醇和 PPAR 激活脂肪酸。我们之前曾表明，用 的脂质提取物进行饮食补充可防止 AD 小鼠模型中的疾病进展，而不会引起与合成泛 LXR 激动剂相关的不良反应。我们现在使用双荧光素酶报告基因测定法确定了六种欧洲褐藻物种 (,,,, 和 ) 和亚洲褐藻 Sargassum fusiforme 的脂质提取物的 LXRα/β 和 PPARα/γ 激活能力。我们分别通过 GC-MS 和 UPLC MS/MS 分析提取物中的甾醇和脂肪酸谱，并使用定量 PCR 确定它们对几种细胞系中 LXR 和 PPAR 靶基因表达的影响。所有提取物均被发现可激活 LXR， 提取物的效果最为明显，与 相比，对 LXR 激活和 LXR 靶基因的转录调节作用相当。Alaria esculenta、Fucus vesiculosus 和 Saccharina latissima 的提取物显示出最高的激活 PPARα 的能力，而 、 、 、 、 、 和 的提取物显示出最高的激活 PPARγ 的能力，与 提取物相当。在 CCF-STTG1 星形胶质细胞瘤细胞中，所有提取物均诱导胆固醇流出基因 ( 、 和 ) 的表达，并抑制胆固醇和脂肪酸合成基因 ( 、 、 和 、 、 和 、 、 和 、 、 和 、 、 的表达)。我们的数据表明，欧洲褐藻的亲脂性部分激活 LXR 和 PPAR，从而调节脂质代谢。这些结果支持褐藻在预防和/或治疗神经退行性疾病以及通过同时激活 LXR 和 PPAR 可能治疗心血管代谢和炎症性疾病方面的潜力。
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