Abstract 420: Lysosomal Acid Lipase Deficiency Impairs Reverse Cholesterol Transport From Macrophages in LAL-Deficient Mice
Bibliographic record
Abstract
The rate of flux of cholesterol out of lysosomes is a key regulator of oxysterol formation and subsequent activation of liver X-receptor to upregulate genes involved in reverse cholesterol transport (RCT). We previously demonstrated impaired regulation of the lipid transporter ATP-binding cassette transporter A1 (ABCA1), required to promote removal of cholesterol from cells and high density lipoprotein (HDL) particle formation, in the lysosomal cholesterol storage disorders Niemann Pick Disease Type C and Cholesteryl Ester Storage Disease, thus providing an explanation for the low plasma HDL-C seen in these diseases. To determine the importance of lysosomal acid lipase (LAL) in reverse cholesterol transport (RCT) from macrophages to feces in vivo, we performed intraperitoneal injection of immortalized peritoneal macrophages from LAL+/+ or LAL-/- mice that had been cholesterol loaded and labeled with acetylated LDL containing 3H-cholesteryl oleate into LAL+/+ and LAL-/- mice, respectively. LAL-/- macrophages exhibited reduced basal and cholesterol-stimulated ABCA1 expression in culture, and reduced ability to support RCT in LAL-/- mice (1.55 ± 0.35 % total injected 3H-cholesterol counts appearing in feces over 48 h, n=30) compared to LAL+/+ macrophages injected into LAL+/+ mice (5.38 ± 0.92 % 3H-cholesterol counts in feces at 48 hr, n=27), p < 0.001. Injection of LAL-/- macrophages into LAL+/+ mice resulted in partial correction of RCT (2.60 ± 0.46 % 3H-cholesterol counts in feces at 48 hr, n=19), p < 0.001 when compared to injection into LAL-/- mice. ABCA1 protein expression was reduced in lal-/- mouse liver and mRNA expression of several LXR-dependent genes involved in reverse cholesterol transport (ABCG1, ABCG5, ABCG8, CYP7A1, SR-B1) were differentially modulated compared to LAL+/+ controls. The results indicate a critical role of macrophage LAL in promoting ABCA1 expression and RCT in vivo, and the ability of secreted LAL to be taken up by macrophages and correct RCT in vivo. The premature atherosclerosis seen in LAL-deficient humans may therefore be reduced by correction of LAL deficiency.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 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".