FoxA2 Mediates Monosaccharide-Induced Repression of SHBG Gene Expression by Regulating Lipid Homeostasis in HepG2 Cells.
Bibliographic record
Abstract
Plasma levels of sex hormone-binding globulin (SHBG) are linked to infertility and risk for the metabolic syndrome. Previously, we found that increased exposures to monosaccharide induces hepatic palmitate accumulations and reduces human SHBG gene expression by down-regulating hepatocyte nuclear factor 4 alpha (HNF-4A) in transgenic mice and HepG2 hepatoblastoma cells. Here, we show that forkhead box A2 (FoxA2) participates in this regulatory pathway. Knock-down of Foxa2 by siRNA increased SHBG gene transcription and SHBG secretion, as tested by luciferase reporter assay and immunofluorometric assay, respectively, in HepG2 cells, while over-expression of FoxA2 had the opposite effect. To test if the effect of FoxA2 on SHBG expression in these cells is direct or indirect, we measured HNF-4A, a key regulator of SHBG transcription, levels in FoxA2 knocked-down or over-expressing cells, and found that FoxA2 is negatively associated with HNF-4A levels, which suggests that FoxA2 regulates SHBG production indirectly through HNF-4A. Since FoxA2 is a key regulator of hepatic lipid homeostasis, we further tested whether FoxA2 could participate in this regulatory pathway. When incubating HepG2 cells in high (10 mM) glucose, knock-down of FoxA2 attenuated glucose-induced repression of HNF-4A and SHBG levels by changing intra-cellular lipid accumulations. In summary, our results indicate that FoxA2 regulates hepatocyte lipid homeostasis, and in turn alters SHBG production at a transcriptional level through HNF-4A. Further studies of FoxA2-regulated alterations in lipid profiles within HepG2 cells are underway. These observations provide further insight the molecular mechanism responsible for altered hepatic SHBG expression in response to changes in nutritional status, and during different physiological conditions. Supported by an operating grant from the Canadian Institutes of Health Research. (poster)
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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".