Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARα and transcription at the <i>Hmgcs2</i> PPRE
Bibliographic record
Abstract
Excessive liver production of ketone bodies is one of many metabolic complications that can arise from diabetes, and in severe untreated cases, it can result in ketoacidosis, coma, and death. Mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting enzyme in ketogenesis, has been shown to interact with PPARalpha and act as a coactivator to up-regulate transcription from the PPRE of its own gene. Although protein palmitoylation is typically a cytosolic process that promotes membrane association, we recently identified 21 palmitoylated proteins in rat liver mitochondria, including HMGCS2. Herein, our data support a mechanism whereby palmitate is first added onto HMGCS2 active site Cys166 and then transacylated to Cys305. Palmitoylation promotes the HMGCS2/PPARalpha interaction, resulting in transcriptional activation from the Hmgcs2 PPRE. These results, together with the fact that 8 of the 21 palmitoylated mitochondrial proteins that we previously identified have nuclear receptor interacting motifs, demonstrate a novel--and perhaps ubiquitous--role for palmitoylation as a modulator of transcription.
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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".