Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases

Zhan, Na; Wang, Boyang; Martens, Nikita; Liu, Yankai; Zhao, Shangge; Voortman, Gardi; Rooij, Jeroen van; Leijten, Frank; Vanmierlo, Tim; Kuipers, Folkert; Jonker, Johan W.; Bloks, Vincent W.; Lütjohann, Dieter; Palumbo, Maria Michela; Zimetti, Francesca; Adorni, Maria Pia; Liu, Hongbing; Mulder, Monique

doi:10.3390/ijms24021290

Cited by 7 publications

(4 citation statements)

References 84 publications

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“…Lipid extracts of the seaweed Sargassum fusiforme (S. fusiforme), which contain LXR-activating (oxy)phytosterols such as saringosterol, have been found to activate LXRs and prevent cognitive decline in AD mice [24]. Recently, we also identified (3β,22E)-3-hydroxycholesta-5,22-dien-24-one and fucosterol-24,28 epoxide as LXR agonists in S. fusiforme [25]. Unlike synthetic LXR agonists, these S. fusiforme extracts did not have adverse effects on hepatic or serum lipid levels, making them a promising alternative for clinical use [24,26].…”

Section: Introductionmentioning

confidence: 99%

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

Martens,

Zhan,

Voortman

et al. 2023

Nutrients

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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.

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Section: Introductionmentioning

confidence: 99%

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

Martens,

Zhan,

Voortman

et al. 2023

Nutrients

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“…For an active state, SREBP1c has to be cleaved from its 130 kDa precursor form located in the ER membrane to an active 60 kDa protein that can translocate into the nucleus. 38 Unlike synthetic LXR agonists, sterol-like LXR ligands appear to be weaker activators of the SREBP1c transcription, particularly in liver cells, 24 , 26 , 27 , 29 , 32 although some ligands can also selectively upregulate SREBP1c expression 39 or function as context-specific antagonists. 40 Furthermore, sterols and oxysterols were shown to inhibit the proteolytic activation of SREBP1c by binding to the SREBP cleavage-activating protein (SCAP) and insulin-induced gene 2 protein (INSIG2), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Limonoids isolated from T. prieuriana , especially those with a ring-intact structure ( 1 – 3 , Chart ), share a four-ring core structure similar to sterol-like LXR ligands. Among those with reported agonistic activity are desmosterol, , a precursor in the cholesterol synthesis pathway, endogenous and synthetic oxysterols, and other sterol derivatives, ,,− as well as natural products of the triterpene type. − This prompted us to investigate whether some limonoids are LXR agonists as well.…”

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confidence: 99%

Flindissone, a Limonoid Isolated from Trichilia prieuriana, Is an LXR Agonist

Resetar,

Tietcheu Galani,

Tsamo

et al. 2023

J. Nat. Prod.

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In this study, the ability of six limonoids from Trichilia prieuriana (Meliaceae) to activate the liver X receptor (LXR) was assessed. One of these limonoids, flindissone, was shown to activate LXR by reporter-gene assays. Flindissone is a ring-intact limonoid, structurally similar to sterol-like LXR ligands. In endogenous cellular settings, flindissone showed an activity profile that is characteristic of LXR agonists. It induced cholesterol efflux in THP-1 macrophages by increasing the cholesterol transporter ABCA1 and ABCG1 gene expression. In HepG2 cells, flindissone induced the expression of IDOL, an LXR-target gene that is associated with the downregulation of the LDL receptor. However, unlike synthetic and similarly to sterol-based LXR agonists, flindissone did not induce the expression of the SREBP1c gene, a major transcription factor regulating de novo lipogenesis. Additionally, flindissone also appeared to be able to inhibit post-translational activation of SREBP1c. The results presented here reveal a natural product as a new LXR agonist and point to an additional property of T. prieuriana and other plant extracts containing flindissone.

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“…It has been demonstrated that treatment with agonists for LXR and RXR leads to an increase in the levels of ABCA1 and APOE, as well as a reduction in amyloid deposition in the brains of mice overexpressing the APP [ 67 , 68 ]. Notably, 24-OHC, serving as a natural endogenous agonist of LXRs, has been shown to induce the up-regulation of ABCA1, ABCG1, and APOE expression [ 69 , 70 ]. Given the findings from the present study, which demonstrated an elevation in the brain levels of 24-OHC following exercise in APP/PS1 mice, we subsequently investigated alterations in nuclear transcription factors associated with cholesterol transport within the brain of APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice

Yuan

Tong

et al. 2023

IJMS

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Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer’s disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

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Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases

Cited by 7 publications

References 84 publications

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

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

Flindissone, a Limonoid Isolated from Trichilia prieuriana, Is an LXR Agonist

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice

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