Abstract 73: A Novel Lysosome-Mediated Degradation Mechanism for Hepatic Lipid Droplet Turnover
Bibliographic record
Abstract
Dietary supplementation with fish oil, rich in n-3 fatty acids such as EPA (20:5n-3), has been shown in many studies to exert a hypotriglyceridemic effect by reducing both plasma triglycerides (TG) in the form of VLDL and intrahepatic TG that is presented in cytoplasm as lipid droplets. However, cellular or molecular mechanisms by which n-3 fatty acid treatment could reduce hepatic TG remain to be defined. We used a well-characterized cell culture system that possesses the ability to synthesize and secreted TG-rich VLDL1 to determine the effect of EPA treatment on the synthesis, storage, turnover, and secretion of TG. Robust accumulation of lipid droplets occurs when hepatic cells were cultured under lipid-rich conditions, and prolonged exposure of the cells to lipids could lead to impaired TG secretion and steatosis. Treatment of the lipid-laden cells with EPA effectively cleared the storage lipid droplets within a few hours. The enhanced turnover of lipid droplets in EPA-treated cells was not attributable to increased TG secretion, because EPA-treatment also impaired VLDL1 assembly/secretion. The droplet turnover required the activity of lysosomes and could be blocked either by NH4Cl treatment or by silencing LAMP1 or Rab7. Inactivation of Atg5, ATGL, or HSL had no effect on the droplets turnover, indicating that the process is independent of autophagosome formation or cytosolic lipase activities. Live cell imaging of cells treated with EPA showed dynamic “kiss-and-run” events between lysosomes and the droplets, which were accompanied with augmented beta-oxidation. Treatment of cells with nocodazole or silencing the Rab7 effctors FYCO1 and RILP, respectively, completely blocked the EPA-induced droplet turnover, suggesting that the movement of lysosomes was essential for the kiss-and-run process. Moreover, overexpression of Arl8b, a lysosome-associated Arf-like GTPase, markedly accelerated the EPA-induced droplet turnover. These results reveal a novel mechanism responsible for the hypolipidemic effect of n-3 fatty treatment, and suggest a therapeutic potential for n-3 fatty acids in the treatment of hepatosteatosis.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.003 |
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".