Differential role for hepatic glucuronidation and sulfonation in controlling the 24S- hydroxycholesterol ability activate LXR
Bibliographic record
Abstract
24S-hydroxycholesterol (24SOH-Chol) is a bioactive cholesterol metabolite formed in the brain. This endogenous activator of the cholesterol sensor, liver X receptor (LXR) is abundantly found as a sulfate-glucuronide diconjugate in the human plasma. The present study characterizes the human sulfonating (SULT) and glucuronidating (UGT) enzymes; and evaluates how these enzymes impact its ability to bind to and activate LXR. In vitro enzymatic assays identified the human SULT2A1 and UGT1A4 as the major isoforms for hepatic 24SOH-Chol sulfonation and glucuronidation, respectively. Additional assays demonstrated that 24SOH-Chol-3Sulfate,24Glucuronide formation requires the successive involvement of UGT1A4 and SULT2A1. TR-FRET and transient transfection experiments revealed that glucuronidation, but not sulfonation, inactivates 24SOH-Chol. Exposure of human liver cells and humanized UGT1 mice to LXR ligands identified UGT1A4, but not SULT2A1, as a positively regulated LXR target gene, while chromatin immunoprecipitation assays, luciferase reporter and siRNA knock down assays demonstrated the ability of LXR to bind to and activate the human UGT1A4 gene promoter. The present study establishes the complementary roles played by SULT2A1 and UGT1A4 in 24SOH-Chol conjugation. We also identify glucuronidation as a mechanism allowing this cholesterol derivative to self-stimulate its own inactivation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".