Inhibition of Low density Lipoprotein Internalization and Transcytosis by HDL; an alternative role for “good” cholesterol
Bibliographic record
Abstract
Atherosclerosis results from the build‐up of low‐density lipoprotein (LDL) cholesterol and immune cells in the arteries leading to their occlusion. High‐density lipoprotein (HDL) is believed to reverse this process by removing the arterial cholesterol from the body. Both LDL and HDL reach beneath the artery by crossing the endothelium through Scavenger receptor B1 (SR‐B1) mediated transcytosis. ApoAI, the protein exclusively found on HDL, mediates the interaction between HDL and SR‐B1. One natural ApoAI variant called Milano (ApoAI‐Mil) is of interest because injections of lipidated ApoAI‐Mil led to enhanced plaque regression. We hypothesize that the natural ability of ApoAI‐Mil to dimerize leads to better interaction with SR‐B1. This could result in better inhibition of LDL transcytosis since both HDL and LDL bind to SR‐B1 for transcytosis and this could also improve HDL transcytosis so that more HDL will reach the target tissue to extract cholesterol. We took an in vitro microscopy approach to quantify internalization of fluorescently labeled LDL in coronary endothelial cells. The ApoAI variants were also lipidated to form fluorescent HDL‐like particles (DiI‐DMPC‐WT or DiI‐DMPC‐Mil) to measure its association with SR‐B1 overexpressing cells. We observed that recombinant ApoAI‐WT can inhibit LDL internalization in coronary endothelial cells. There was also about an 8x‐fold increase of DiI‐DMPC‐WT fluorescence signal in HeLas overexpressing SR‐B1 compared to GFP alone. Furthermore, there was an even higher fold increase (~11x) of DiI‐DMPC‐Mil fluorescence signal compared to GFP alone. Similarly, excess recombinant ApoAI‐Mil led to greater inhibition of LDL internalization compared to ApoAI‐WT. There was no difference in the amount of DiI‐DMPC‐WT or ‐Mil associated with HeLa cells overexpressing Alk1, a LDL‐specific transcytosis receptor. Together this suggests that compared to ApoAI‐WT, ApoAI‐Mil more readily associates with only SR‐B1 which may lead to better inhibition of LDL internalization and to more HDL available to remove arterial cholesterol. Support or Funding Information Early Research Award & CIHR
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".