Vitamin D and Lumisterol Hydroxyderivatives Can Act on Liver X Receptors (LXRs)
Bibliographic record
Abstract
Abstract New pathways of vitamin D3 (D3) activation initiated by CYP11A1 and involving other CYPs have been discovered. At least 15 hydroxyderivatives, including 20(OH)D3 as the major product, are generated by these pathways (1,2) with some being present in human serum, epidermis, and pig adrenals. CYP11A1 can also metabolize 7-dehydrocholesterol to produce 7-dehydropregnenolone, which can be further modified by steroidogenic enzymes generating Δ7-steroids (1,2). Lastly, CYP11A1 and CYP27A1 act on lumisterol (L3) producing at least 9 biologically active derivatives (1,2). Thus, new pathways generating a large number of biologically active secosteroids and lumisterol-derivatives have now been described. These compounds interact with the vitamin D receptor (VDR), retinoic acid receptors (RORs) α and γ, and the aryl hydrocarbon receptor (AhR)(1). These findings challenge dogmas that lumisterol is biologically inactive and that 1,25(OH)2D3 is the only active form of D3 exerting its effects exclusively through interaction with the VDR. In view of the above and since liver X receptors (LXRs) can be activated by oxysterols, we investigated the interactions of novel products of L3 and D3 metabolism with LXRs. Molecular docking, using crystal structures of the ligand binding domains (LBDs) of LXRα and β, revealed high docking scores for L3 and D3 hydroxymetabolites, like those of the natural ligands, predicting good receptor binding. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second major nuclear receptor signaling pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. The involvement of LXRs was validated by the induction of several genes downstream of LXR. Furthermore, L3 and D3-hydroxyderivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes. For keratinocytes, enhanced expression of LXR target genes was also observed supporting the involvement of LXR. Importantly, L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. The majority of metabolites functioned as LXRα/β agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRβ. Molecular dynamics simulations performed for selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed overlapping and different interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs changes the accepted paradigms on their biological role and mechanism of action. 1. Cell Biochem Biophys. 2020;78(2):165-180. 2. J Steroid Biochem Mol Biol. 2019;186:4-21.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".