Abstract 5: Sortilin Regulates Hepatic VLDL Secretion and LDL Uptake in a Lysosome-Dependent Manner
Bibliographic record
Abstract
Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of sortilin on both VLDL secretion and LDL turnover is dependent on the ability of sortilin to traffic to the lysosome, as sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between sortilin and the apoB in LDL particles at physiological pH with a K d of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic sortilin overexpression in humans with reduced plasma cholesterol.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".