Abstract 509: Apolipoprotein(a) and ApolipoproteinB Co-localize and Interact Intracellularly in Lipoprotein(a) Biosynthesis
Bibliographic record
Abstract
Lipoprotein(a) (Lp(a)) is an LDL-related particle distinguished by the presence of apolipoprotein(a) (apo(a)). Elevated plasma Lp(a) levels conferring increased risk for atherosclerotic cardiovascular and calcific aortic valve diseases occur in more than 20% of the global population. As such, novel approaches to Lp(a) lowering including inhibition of the formation of the particle should be explored. However, the location of Lp(a) assembly - intracellularly in hepatocytes or extracellularly - remains unclear. Apo(a) and apoB100 initially interact non-covalently via the weak lysine binding sites in apo(a) kringle IV types 7 and 8 and lysine residues in apoB; this facilitates formation of the covalent bond between apo(a) and apoB to form the Lp(a) particle. We hypothesize that apo(a) non-covalently interacts with apoB intracellularly, with disulfide bond formation occurring extracellularly, possibly on the hepatocyte cell surface. If true, Lp(a) biosynthesis would be enhanced by promoting lipidation of apoB. To examine these hypotheses, human hepatoma (HepG2) cells stably expressing a 17 kringle-containing form of apo(a) were grown in absence or presence of 0.5 mM oleic acid (OA); cell lysates and media were then subjected to co-immunoprecipitation analysis using apo(a)- and apoB-specific antibodies. A non-covalent complex containing apo(a) and apoB was present in both lysates and media, whereas covalent apo(a)/apoB complexes were only present in the media. Interestingly, OA enhanced apo(a)/apoB secretion, with increased recovery of non-covalent and covalent Lp(a) complexes observed. In confocal microscopy experiments, where apo(a) and apoB colocalized intracellularly they consistently overlapped with staining for the ER marker calnexin and the trans-Golgi marker TGN46, but not with the lysosomal marker LAMP1 or the early endosome marker EEA1. In conclusion, apo(a) and apoB interact non-covalently within the secretory pathway of HepG2 cells, which explains why enhancing lipidation of apoB promotes apo(a)/Lp(a) secretion, although covalent complex formation is exclusively extracellular. These findings may underlie the ability of agents that inhibit apoB biosynthesis, such as mipomersen and lomitapide, lower Lp(a) levels.
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.007 |
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".