Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations

Viktorsson, Elvar Örn; Gabrielsen, Mari; Kumarachandran, Nugalya; Sylte, Ingebrigt; Rongved, Pål; Åstrand, Ove Alexander Høgmoen; Kase, Eili Tranheim

doi:10.1016/j.steroids.2016.12.003

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Oxysterols have been known to act as ligands of the LXR nuclear receptors [ 24 ]; therefore, we assessed whether these receptors are associated with the osteogenic effect of oxysterols. Western blotting analysis detected increased protein levels of LXRα and LXRβ (isoforms of LXRs) in response to SS treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models

et al. 2017

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BackgroundOxysterols, oxygenated by-products of cholesterol biosynthesis, play roles in various physiological and pathological systems. However, the effects of oxysterols on periodontal regeneration are unknown. This study investigated the effects of the specific oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol (SS) on the regeneration of periodontal tissues using in-vitro periodontal ligament stem cells (PDLSCs) and in-vivo models of alveolar bone defect.MethodsTo evaluate the effects of the combined oxysterols on PDLSC biology, we studied the SS-induced osteogenic differentiation of PDLSCs by assessing alkaline phosphatase activity, intracellular calcium levels [Ca2+]i, matrix mineralization, and osteogenic marker mRNA expression and protein levels. To verify the effect of oxysterols on alveolar bone regeneration, we employed tooth extraction bone defect models.ResultsOxysterols increased the osteogenic activity of PDLSCs compared with the control group. The expression of liver X receptor (LXR) α and β, the nuclear receptors for oxysterols, and their target gene, ATP-binding cassette transporter A1 (ABCA1), increased significantly during osteogenesis. Oxysterols also increased protein levels of the hedgehog (Hh) receptor Smo and the transcription factor Gli1. We further confirmed the reciprocal reaction between the LXRs and Hh signaling. Transfection of both LXRα and LXRβ siRNAs decreased Smo and Gli1 protein levels. In contrast, the inhibition of Hh signaling attenuated the LXRα and LXRβ protein levels. Subsequently, SS-induced osteogenic activity of PDLSCs was suppressed by the inhibition of LXRs or Hh signaling. The application of SS also enhanced bone formation in the defect sites of in-vivo models, showing equivalent efficacy to recombinant human bone morphogenetic protein-2.ConclusionsThese findings suggest that a specific combination of oxysterols promoted periodontal regeneration by regulating PDLSC activity and alveolar bone regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0725-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models

et al. 2017

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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 . Unlike synthetic LXR agonists, sterol-like LXR ligands appear to be weaker activators of the SREBP1c transcription, particularly in liver cells, ,,,, although some ligands can also selectively upregulate SREBP1c expression or function as context-specific antagonists . 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%

“… 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. In a sterol-bound state, these two chaperones anchor the inactive SREBP1c precursor to the ER membrane.…”

Section: Resultsmentioning

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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“…This kind of selectivity makes 79 a good candidate for further studies as an antiatherosclerotic drug. In contrast, the Fernholtz cyclohexylamide ( 80 ) downregulated the de novo lipogenesis in a dose-dependent manner and counteracted the effect of 1 on LXR …”

Section: Medicinal Chemistry Of Lxr Modulatorsmentioning

confidence: 99%

“…In contrast, the Fernholtz cyclohexylamide (80) downregulated the de novo lipogenesis in a dose-dependent manner and counteracted the effect of 1 on LXR. 106 Recently, Astrand et al developed a series of LXRβ antagonists using a molecular modeling approach. The structures of these antagonists were based on the selective antagonist 22SHC (81).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Recent Advances in the Medicinal Chemistry of Liver X Receptors

et al. 2018

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Nuclear hormone receptors represent a large family of ligand-activated transcription factors that include steroid receptors, thyroid/retinoid receptors, and orphan receptors. Among nuclear hormone receptors, the liver X receptors have emerged as very important drug targets. These receptors regulate some of the most important metabolic functions, and they were also identified as anti-inflammatory transcription factors and regulators of the immune system. The development of drugs targeting liver X receptors continues to be a challenge, but advances in our knowledge of receptor structure and function move us forward, toward achieving this goal. This review highlights the latest advances in the development of synthetic LXR modulators in the primary literature from 2013 to 2017. In this review, we place great emphasis on the structure and function of LXRs because of their essential role in the drug design process. The structure-activity relationships of the most active and promising synthetic modulators are discussed.

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Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations

Cited by 8 publications

References 42 publications

Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models

Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models

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

Recent Advances in the Medicinal Chemistry of Liver X Receptors

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