Abstract 537: Characterization of the Lipase Stimulating Domain for Apolipoprotein A-V and the Development of a Therapeutic Peptide for the Treatment of Hypertriglyceridemia
Bibliographic record
Abstract
The impaired clearance of plasma triglycerides is a major cause of clinical hypertriglyceridemia, a condition which affects about one third of adults in the G7 countries and is a risk factor for a number of diseases, including cardiovascular disease, cancer and pancreatitis. The hydrolysis and removal of triglycerides from the plasma is dependent on cell surface lipoprotein lipase (LpL) and its enzymatic activity is in turn regulated by specific apolipoproteins; apoC-III, which acts as a potent inhibitor and apoC-II and apoA-V, which act as stimulators. Their importance in hypertriglyceridemia is underscored by GWAS analyses, which have identified the APOA1/C3/A4/A5 gene cluster (chromosome 11q23) as an important determinant of dylipidemia. ApoA-V is of particular interest since its physiological concentration (3.8 nM) is 10,000x lower than that of apoC-II and the other major apolipoproteins. To investigate the influence of different lipoproteins on lipase kinetics we have developed a fluorescence-based assay that uses a fluorogenic triglyceride analog (EnzChek®) in a microplate format. Here we report that a short alpha-helical amphipathic peptide (AV199-232) corresponding to apoA-V residues 199-232 exhibit; i) lipid-binding, ii) heparin-binding and iii) lipase-stimulating activities. Structural characterization and residue substitution studies have been employed to map these three activities to three separate discrete domains within AV199-232. Enzyme kinetic analysis with pure LpL indicates that AV199-232 can overcome the inhibition of LpL by apoC-III and stimulate enzyme activity by reducing its Km 8-fold. Similar increases in lipase activity are also observed with live THP-1 monocytes and HepG2 cells that express hepatic lipase. The influence of AV199-232 in cell culture is saturable, dependent on the presence of cell surface lipase, and enzymatic activation can be sustained for at least 2 hrs. We postulate that apoA-V and AV199-232 stimulate lipase activity through an allosteric mechanism by binding to lipases with high affinity near their catalytic site to affect enzyme kinetics.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".