Abstract 437: Lipoprotein(a) Internalization in HepG2 Cells is Regulated by Proprotein Convertase Subtilisin Kexin Type 9 Through the Low-Density Lipoprotein Receptor
Bibliographic record
Abstract
Elevated levels of lipoprotein(a) (Lp(a)) have been identified as an independent and causal risk factor for coronary heart disease. Lp(a) consists of an LDL-like moiety covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). The mechanism by which Lp(a) is catabolized is currently unknown, but may form the basis for the development of drug therapy to reduce high levels of plasma Lp(a). Although the role of the LDL receptor (LDLR) in Lp(a) catabolism is controversial, recent evidence has shown that Lp(a) levels are significantly reduced with an antibody against proprotein convertase subtilisin kexin type 9 (PCSK9) in patients with hypercholesterolemia receiving statin therapy. Therefore, we explored the role of PCSK9 in Lp(a)/apo(a) internalization by hepatic cells. Lp(a) or apo(a) internalization is significantly reduced in HepG2 (human hepatoma) cells either by overexpressing PCSK9 or by treatment with purified PCSK9. The ability of Lp(a) and apo(a) to be internalized was significantly reduced in the presence of the lysine analogue, ε-ACA, indicating lysine-dependent interactions with cellular receptors. Mutation of the strong lysine binding site in a recombinant apo(a) variant resulted in a reduced ability to be internalized. While LDL can bind to PCSK9 and inhibit its ability to degrade the LDLR, we found that Lp(a) lacked these properties. Interestingly, overexpressing the LDLR on HepG2 cells significantly increased the ability of Lp(a) to be internalized, an effect that was partially reduced by the addition of PCSK9. This indicates a potential key role for the LDLR in regulating Lp(a) catabolism. Furthermore, knockdown of clathrin heavy chain resulted in a significant decrease in apo(a) internalization and apo(a) internalization was not further reduced by pre-treatment of PCSK9 in the context of clathrin heavy chain knockdown. Treatment of HepG2 cells with a lysosomal inhibitor, but not a proteosomal inhibitor, resulted in accumulation of Lp(a) in HepG2 cells indicating that Lp(a) is potentially targeted for degradation through lysosomes. Taken together, these results indicate that Lp(a)/apo(a) uptake can be regulated in HepG2 cells by PCSK9 and the LDLR through clathrin-mediated endocytosis and lysosomal degradation.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".