Regulation of Cytochrome P450 3A4 in Non‐Alcoholic Fatty Liver Disease by Fibroblast Growth Factor 21
Bibliographic record
Abstract
Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease affecting approximately one third of adults. For a majority of NAFLD patients, the associated metabolic syndrome necessitates drug therapy for management of diabetes, dyslipidemia and hypertension. Interestingly, while many drugs used by patients with NAFLD are eliminated from the body by hepatic drug metabolism, little is known regarding the effect of steatosis on hepatic drug metabolism and drug response. We have previously shown that Cytochrome P450 (CYP) 3A4 metabolic activity and expression are reduced in patients with NAFLD as well as in mouse and in vitro models of hepatic steatosis. Here, we investigated the role of the lipid‐ and glucose‐modulating hormone, Fibroblast Growth Factor 21 (FGF21), in the molecular mechanism regulating CYP3A4 expression in NAFLD. We confirmed that levels of circulating FGF21 are elevated in NAFLD patients. Using a cultured, human hepatoma cell (Huh7) model, we found forced steatosis caused a 4‐fold induction of FGF21 expression and a 50% decrease in CYP3A4 mRNA. Chemical inhibition of the canonical MAPK/ERK phosphorylation cascade triggered by FGF21, resulted in increased CYP3A4 expression. FGF21 treatment was associated with decreased nuclear localization of the CYP3A4 gene‐regulating transcription factors PXR, CAR. Moreover, transcription factor binding to the CYP3A4 promoter was reduced with FGF21 treatment. We conclude that FGF21 is involved in decreased hepatic drug metabolism in NAFLD. These findings are expected to provide the basis for further studies aimed at optimizing pharmacotherapy in NAFLD.
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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".