Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice
Bibliographic record
Abstract
UNLABELLED: Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase enzyme in the triglyceride synthesis pathways and a transcriptional coregulator. Our previous studies have shown that ethanol causes fatty liver by activation of sterol regulatory element-binding protein 1 (SREBP-1) and inhibition of hepatic AMP-activated protein kinase (AMPK) in mice. Here, we tested the hypothesis that AMPK-SREBP-1 signaling may be involved in ethanol-mediated up-regulation of lipin-1 gene expression. The effects of ethanol on lipin-1 were investigated in cultured hepatic cells and in the livers of chronic ethanol-fed mice. Ethanol exposure robustly induced activity of a mouse lipin-1 promoter, promoted cytoplasmic localization of lipin-1, and caused excess lipid accumulation, both in cultured hepatic cells and in mouse livers. Mechanistic studies showed that ethanol-mediated induction of lipin-1 gene expression was inhibited by a known activator of AMPK or overexpression of a constitutively active form of AMPK. Importantly, overexpression of the processed nuclear form of SREBP-1c abolished the ability of 5-aminoimidazole-4-carboxamide ribonucleoside to suppress ethanol-mediated induction of lipin-1 gene-expression level. Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene. CONCLUSION: In conclusion, ethanol-induced up-regulation of lipin-1 gene expression is mediated through inhibition of AMPK and activation of SREBP-1.
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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".