Abstract 1056: Overexpression Of Lysosomal Acid Lipase
Bibliographic record
Abstract
Background: Previous evidence suggests arterial smooth muscle cells (SMCs) comprise the majority of atherosclerotic lesion foam cells in human and mouse atheromas, have reduced expression of ABCA1 and lysosomal acid lipase (LAL) compared to macrophages, and retain cholesteryl esters in lysosomes rather than in the cytoplasm as in macrophage foam cells. Exogenous LAL can increase cholesterol efflux from SMC foam cells despite low ABCA1. Hypothesis: Overexpression of LAL increases cholesterol efflux from SMC foam cells by ABCA1-dependent and -independent mechanisms. Methods: Human vascular SMCs were transfected with 500 MOI AdV- LIPA or AdV- mCherry (adenovirus) control for 6 h and cholesterol loaded using 100 μg/ml aggregated LDL (agLDL) for 24 h. LAL activity was measured by specific enzymatic assay and location of stored cholesteryl esters (CE) was determined using LAMP-1 (lysosome marker) and BODIPY (neutral lipid) staining by confocal microscopy. Cholesterol efflux to 10 μg/ml apoliprotein A-I (ApoA-I) or 100 μg/ml HDL was determined following ABCA1 siRNA treatment or control, with cholesterol mass determined using Amplex Red assay. Student’s t test was used for statistical analysis of LAL activity, and Mann-Whitney U Test for analysis of colocalization of lipid pools. Results: LAL activity increased 1.67-fold 72 h after transfection with AdV- LIPA compared to SMCs transfected with AdV- mCherry (n=5, p = 0.001). Increased LAL expression in the absence of cholesterol acceptor resulted in a shift in CE storage from lysosomes to non-lysosomal compartments (Pearson correlation coefficient for BODIPY/LAMP-1 colocalization 0.27 in AdV- LIPA vs. 0.47 in AdV- mCherry SMCs, n=103, p < 0.00001). Preliminary cholesterol efflux studies indicate SMCs overexpressing LAL release cholesterol by both ABCA1-dependent and -independent mechanisms. Conclusion: Our study provides evidence that despite low ABCA1 and LAL expression, SMC foam cells mobilize lysosomal cholesterol for cellular trafficking and efflux following supplementation with LAL. Further studies will examine changes in gene expression and the mechanism of ABCA1-independent efflux following LAL supplementation in SMC foam cells.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.004 |
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".