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20(S)-Hydroxycholesterol

Allosteric activator of Hedgehog (Hh) signaling; induces Smo accumulation CAS# 516-72-3

20(S)-Hydroxycholesterol

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Chemical structure

20(S)-Hydroxycholesterol

3D structure

Chemical Properties of 20(S)-Hydroxycholesterol

Cas No. 516-72-3 SDF Download SDF
PubChem ID 121935 Appearance Powder
Formula C27H46O2 M.Wt 402.65
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 30 mg/mL (74.51 mM; ultrasonic and warming and heat to 60°C)
Chemical Name (3S,8S,9S,10R,13S,14S,17S)-17-[(2S)-2-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol
SMILES CC(C)CCCC(C)(C1CCC2C1(CCC3C2CC=C4C3(CCC(C4)O)C)C)O
Standard InChIKey MCKLJFJEQRYRQT-APGJSSKUSA-N
Standard InChI InChI=1S/C27H46O2/c1-18(2)7-6-14-27(5,29)24-11-10-22-21-9-8-19-17-20(28)12-15-25(19,3)23(21)13-16-26(22,24)4/h8,18,20-24,28-29H,6-7,9-17H2,1-5H3/t20-,21-,22-,23-,24-,25-,26-,27-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of 20(S)-Hydroxycholesterol

DescriptionAllosteric activator of the Hedgehog signaling pathway Smoothened (Smo) oncoprotein; binds at a site distinct from the canonical cyclopamine binding site. Activates Hedgehog (Hh) signaling (EC50 ~ 3μM for induction of Hh reporter gene transcription in in NIH 3T3 cells). Induces Smo accumulation in primary cilia; also exhibits osteogenic activity and activates the liver X receptor (LXR).

20(S)-Hydroxycholesterol Dilution Calculator

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20(S)-Hydroxycholesterol Molarity Calculator

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Preparing Stock Solutions of 20(S)-Hydroxycholesterol

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4835 mL 12.4177 mL 24.8355 mL 49.6709 mL 62.0887 mL
5 mM 0.4967 mL 2.4835 mL 4.9671 mL 9.9342 mL 12.4177 mL
10 mM 0.2484 mL 1.2418 mL 2.4835 mL 4.9671 mL 6.2089 mL
50 mM 0.0497 mL 0.2484 mL 0.4967 mL 0.9934 mL 1.2418 mL
100 mM 0.0248 mL 0.1242 mL 0.2484 mL 0.4967 mL 0.6209 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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References on 20(S)-Hydroxycholesterol

Tracking the subcellular fate of 20(s)-hydroxycholesterol with click chemistry reveals a transport pathway to the Golgi.[Pubmed:24596093]

J Biol Chem. 2014 Apr 18;289(16):11095-110.

Oxysterols, oxidized metabolites of cholesterol, are endogenous small molecules that regulate lipid metabolism, immune function, and developmental signaling. Although the cell biology of cholesterol has been intensively studied, fundamental questions about oxysterols, such as their subcellular distribution and trafficking pathways, remain unanswered. We have therefore developed a useful method to image intracellular 20(S)-Hydroxycholesterol with both high sensitivity and spatial resolution using click chemistry and fluorescence microscopy. The metabolic labeling of cells with an alkynyl derivative of 20(S)-Hydroxycholesterol has allowed us to directly visualize this oxysterol by attaching an azide fluorophore through cyclo-addition. Unexpectedly, we found that this oxysterol selectively accumulates in the Golgi membrane using a pathway that is sensitive to ATP levels, temperature, and lysosome function. Although previous models have proposed nonvesicular pathways for the rapid equilibration of oxysterols between membranes, direct imaging of oxysterols suggests that a vesicular pathway is responsible for differential accumulation of oxysterols in organelle membranes. More broadly, clickable alkynyl sterols may represent useful tools for sterol cell biology, both to investigate the functions of these important lipids and to decipher the pathways that determine their cellular itineraries.

20(S)-hydroxycholesterol inhibits PPARgamma expression and adipogenic differentiation of bone marrow stromal cells through a hedgehog-dependent mechanism.[Pubmed:17638575]

J Bone Miner Res. 2007 Nov;22(11):1711-9.

UNLABELLED: Specific oxysterols have been shown to be pro-osteogenic and anti-adipogenic. However, the molecular mechanism(s) by which oxysterols inhibit adipogenic differentiation is unknown. We show that the anti-adipogenic effects of osteogenic oxysterol, 20(S)-Hydroxycholesterol, are mediated through a hedgehog-dependent mechanism(s) and are associated with inhibition of PPARgamma expression. INTRODUCTION: Multipotent bone marrow stromal cells (MSCs) are common progenitors of osteoblasts and adipocytes. A reciprocal relationship between osteogenic and adipogenic differentiation may explain the increased adipocyte and decreased osteoblast formation in aging and osteoporosis. We have previously reported that specific oxysterols stimulate osteogenic differentiation of MSCs while inhibiting their adipogenic differentiation. MATERIALS AND METHODS: The M2-10B4 (M2) murine pluripotent bone MSC line was used to assess the inhibitory effects of 20(S)-Hydroxycholesterol (20S) and sonic hedgehog (Shh) on peroxisome proliferator-activated receptor gamma (PPARgamma) and adipogenic differentiation. All results were analyzed for statistical significance using ANOVA. RESULTS AND CONCLUSIONS: Treatment of M2 cells with the osteogenic oxysterol 20S completely inhibited adipocyte formation induced by troglitazone after 10 days. PPARgamma mRNA expression assessed by RT-qPCR was significantly induced by Tro after 48 (5-fold) and 96 h (130-fold), and this induction was completely inhibited by 20S. In contrast, 20S did not inhibit PPARgamma transcriptional activity in M2 cells overexpressing PPARgamma and retinoid X receptor (RXR). To elucidate the molecular mechanism(s) by which 20S inhibits PPARgamma expression and adipogenic differentiation, we focused on the hedgehog signaling pathway, which we previously showed to be the mediator of osteogenic responses to oxysterols. The hedgehog signaling inhibitor, cyclopamine, reversed the inhibitory effects of 20S and Shh on troglitazone-induced adipocyte formation in 10-day cultures of M2 cells by 70% and 100%, respectively, and the inhibitory effect of 20S and Shh on troglitazone-induced PPARgamma expression was fully reversed at 48 h by cyclopamine. Furthermore, 20S and Shh greatly inhibited PPARgamma2 promoter activity induced by CCAAT/enhancer-binding protein alpha overexpression. These studies show that, similar to the induction of osteogenesis, the inhibition of adipogenesis in murine MSCs by the osteogenic oxysterol, 20S, is mediated through a hedgehog-dependent mechanism(s).

Osteogenic oxysterol, 20(S)-hydroxycholesterol, induces notch target gene expression in bone marrow stromal cells.[Pubmed:19839776]

J Bone Miner Res. 2010 Apr;25(4):782-95.

We previously reported that specific oxysterols stimulate osteogenic differentiation of pluripotent bone marrow stromal cells (MSCs) through activation of hedgehog (Hh) signaling and may serve as potential future therapies for intervention in osteopenia and osteoporosis. In this study we report that the osteogenic oxysterol 20(S)-Hydroxycholesterol (20S) induces the expression of genes associated with Notch signaling. Using M2-10B4 (M2) MSCs, we found that 20S significantly induced HES-1, HEY-1, and HEY-2 mRNA expression compared with untreated cells, with maximal induction after 48 hours, whereas the nonosteogenic oxysterols did not. Similar observations were made when M2 cells were treated with sonic hedgehog (Shh), and the specific Hh pathway inhibitor cyclopamine blocked 20S-induced Notch target gene expression. 20S did not induce Notch target genes in Smo(-/-) mouse embryonic fibroblasts, further confirming the role of Hh signaling in 20S-induced expression of Notch target genes. Despite the inability of liver X-receptor (LXR) synthetic ligand TO901317 to induce Notch target genes in M2 cells, LXR knockdown studies using siRNA showed inhibition of 20S-induced HEY-1 but not HES-1 expression, suggesting the partial role of LXR signaling in MSC responses to 20S. Moreover, 20S-induced Notch target gene expression was independent of canonical Notch signaling because neither 20S nor Shh induced CBF1 luciferase reporter activity or NICD protein accumulation in the nucleus, which are hallmarks of canonical Notch signaling activation. Finally, HES-1 and HEY-1 siRNA transfection significantly inhibited 20S-induced osteogenic genes, suggesting that the pro-osteogenic effects of 20S are regulated in part by HES-1 and HEY-1.

Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling.[Pubmed:23831757]

Nat Chem Biol. 2013 Sep;9(9):557-64.

Oxysterols bind the seven-transmembrane protein Smo (Smo) and potently activate vertebrate Hedgehog (Hh) signaling, a pathway essential in embryonic development, adult stem cell maintenance and cancer. It is unknown, however, whether oxysterols are important for normal vertebrate Hh signaling and whether antagonizing oxysterols can inhibit the Hh pathway. We developed azasterols that block Hh signaling by binding the oxysterol-binding site of Smo. We show that the binding site for oxysterols and azasterols maps to the extracellular, cysteine-rich domain of Smo and is completely separable from the site bound by other small-molecule modulators, located within the heptahelical bundle of Smo. Smo mutants in which oxysterol binding is abolished no longer respond to oxysterols and cannot be maximally activated by the Hh ligand. Our results show that oxysterol binding to vertebrate Smo is required for normal Hh signaling and that targeting the oxysterol-binding site is an effective strategy to inhibit Smo.

Oxysterols are allosteric activators of the oncoprotein Smoothened.[Pubmed:22231273]

Nat Chem Biol. 2012 Jan 8;8(2):211-20.

Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-Hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms.

Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells.[Pubmed:17200122]

J Biol Chem. 2007 Mar 23;282(12):8959-68.

Pluripotent mesenchymal cells form a population of precursors to a variety of cell types, including osteoblasts and adipocytes. Aging tilts the balance in favor of adipocyte differentiation at the expense of osteoblast differentiation, resulting in reduced bone formation and osteopenic disorders, including osteoporosis, in humans and animals. Understanding the mechanisms involved in causing this apparent shift in differentiation and identifying factors that stimulate osteoblast formation while inhibiting adipogenesis are of great therapeutic interest. In this study we report that specific, naturally occurring oxysterols, previously shown to direct pluripotent mesenchymal cells toward an osteoblast lineage, exert their osteoinductive effects through activation of Hedgehog signaling pathway. This was demonstrated by 1) oxysterol-induced expression of the Hh target genes Gli-1 and Patched, 2) oxysterol-induced activation of a luciferase reporter driven by a multimerized Gli-responsive element, 3) inhibition of oxysterol effects by the hedgehog pathway inhibitor, cyclopamine, and 4) unresponsiveness of Smoothened-/- mouse embryonic fibroblasts to oxysterols. Using Patched-/- cells that possess high baseline Gli activity, we found that oxysterols did not dramatically shift the IC50 concentration of cyclopamine needed to inhibit Gli activity in these cells. Furthermore, binding studies showed that oxysterols did not compete with fluorescently labeled cyclopamine, BODIPY-cyclopamine, for direct binding to Smoothened. These findings demonstrate that oxysterols stimulate hedgehog pathway activity by indirectly activating the seven-transmembrane pathway component Smoothened. Osteoinductive oxysterols are, therefore, novel activators of the hedgehog pathway in pluripotent mesenchymal cells, and they may be important modulators of this critical signaling pathway that regulates numerous developmental and post-developmental processes.

Description

20(S)-hydroxyCholesterol (20α-Hydroxycholesterol) is an allosteric activator of the oncoprotein smoothened (Smo) that activates the hedgehog (Hh) signaling pathway with an EC50 of 3 μM in a gene transcription reporter assay using NIH3T3 cells.

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