Regulation of Hepatic UGT1A4 by Liver X Receptor LXRα, and not LXRβ in <i>hUGT1</i> Mice
Bibliographic record
Abstract
UDP‐glucuronosyltransferases (UGTs) are metabolic enzymes catalyzing the transformation of multiple xeno‐ and endobiotics into their more water‐soluble glucuronides. Among the UGT enzymes, UGT1A4 is known for the N‐glucuronidation of amine containing xenobiotics, including anticonvulsants, antidepressants and environmental mutagens. To examine the function of UGT1A4 and other genes associated with the human UGT1 locus, we have implemented humanized UGT1 mice ( hUGT1 ). In this study we identify UGT1A4 as a positively regulated target gene of the nuclear receptor liver X‐receptor (LXR). LXR is a member of the nuclear receptor superfamily. Two isoforms of LXR exist, LXRα and LXRβ. The treatment of neonatal hUGT1 mice with the conventional LXR agonist T0901317 led to transcriptional activation of downstream LXR target genes, including UGT1A1 , UGT1A4 , Scd1 and Scd2 . Since neonatal hUGT1 mice develop extreme hyperbilirubinemia, the induction of intestinal and liver UGT1A1 led to a dramatic reduction in total serum bilirubin. Repeating the induction patterns in hUGT1/Lxrα −/− and hUGT1/LXRβ −/− mice, expression of Scd1 and Scd2 displayed specificity for LXRα. There was significant induction of these genes in hUGT1/Lxrβ −/− mice with limited activation in hUGT1/Lxrα −/− mice. In contrast, the induction of UGT1A1 and the UGT1A1 gene by T0901317 is regulated by both activated LXRα and LXRβ. However, like Scd1 and Scd2 , induction of the UGT1A4 gene was selective towards LXRα, with greatly reduced expression in hUGT1/Lxrα −/− mice. Induction of the UGT1A4 gene was comparable in hUGT1/Lxrβ +/− and hUGT1/LXRβ −/− mice. Clearly, LXRα and LXRβ can display fine selectivity for downstream target gene activation, such as the UGT1A4 gene. Support or Funding Information USPHS grants GM086713 and ES010337, DFG (German Research Foundation) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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".