1611-P: The Impact of PKC-δ and p38a MAPK on FFA-Induced Hepatic Lipid Metabolic Dysfunction
Bibliographic record
Abstract
Introduction and Objective: Excess plasma free fatty acids (FFAs) seen in obesity have been implicated in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). While previous studies have demonstrated increased PKC-δ activity in FFA-induced insulin resistance and the downstream activation of p38α in FFA-treated hepatocytes, its precise role and mechanisms in mediating FFA-driven hepatic lipid metabolic dysregulation remain unexamined in vivo. Methods: 12-14 wk old wild-type (WT), hepatocyte-specific PKC-δ knockout (PKC-δKO) and p38αMAPK knockout (p38αKO) mice (n≥5 per group) were intravenously infused with either a vehicle or a 2:1 mixture of oleate and palmitate for 48h. After 5h fasting, liver tissue was collected for Oil-Red O staining, western blot and qPCR analyses or 1000mg/kg P407 was administered intraperitoneally to block triglyceride (TG) clearance and thus assess TG secretion. Liver tissue was also collected from WT and p38αKO mice with adenoviral overexpression of PKC-δ. Results: PKC-δKO and p38αKO mice were protected from FFA-induced hepatosteatosis (p<0.05) and increased TG secretion (p<0.05). Additionally, contrary to expectations, we found that hepatocyte-specific p38αKO mice were not protected from PKC-δ induced hepatosteatosis. Under elevated plasma FFA conditions, p38αKO mice showed significantly increased mRNA levels of beta-oxidation genes Acox1, Aco1, Cpt1, Pparα and PKC-δKO mice demonstrated elevated mRNA of Pdk4, also a beta-oxidation gene (p<0.05). Conclusion: PKC-δ and p38α induce hepatic fat accumulation and TG secretion in association with suppression of beta-oxidation gene expression. However, PKC-δ does not induce hepatic fat accumulation via p38α. Therefore, inhibitors targeting both PKC-δ and p38α may prove beneficial in addressing MASLD and the metabolic consequences of increased FFA levels. Disclosure Y.D. Joseph: None. J. Li: Employee; Merck & Co., Inc, ALX Oncology. F. Vlavcheski: None. E. Tsiani: None. C. Cummins: None. A. Giacca: None. Funding Canadian Institutes of Health Research (503010); Ontario Graduate Scholarship; BBDC-Novo Nordisk Studentship
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".