Abstract 22: LDLR Promotes and PCSK9 Inhibits LDL-Derived Transintestinal Cholesterol Excretion
Bibliographic record
Abstract
Direct transintestinal cholesterol excretion (TICE) is an alternative path to biliary secretion and accounts for 33% of fecal cholesterol excretion in mice. Objectives: We aimed at identifying i) the lipoproteins involved in TICE ii) the role of intestinal LDL receptor (LDLR) and of its natural inhibitor, circulating proprotein convertase subtilisin kexine type 9 (PCSK9) at the basolateral pole iii) the implication of ATP binding cassette transporter ABCB1ab, a cholesterol floppase localized at the enterocytes apical side. Methods: We labelled human lipoproteins with free 3H cholesterol (free3H) or with 3H-cholesteryl oleate (3HCO). We measured lipoprotein-derived 3H-cholesterol TICE ex vivo in intestinal explants mounted in Ussing chambers. Human explants were obtained from 4 patients undergoing bariatric surgery with their informed consent. In vivo, TICE was measured in mice i.v. injected with radiolabelled lipoproteins, by cannulation of the proximal intestine and concomitant surgical bile diversion, counting radioactivity in intestinal perfusates over 120 minutes. Results: For the first time, we showed direct evidence of TICE in human duodenal explants, from both LDL and HDL. Both lipoproteins (labelled with free3H or 3HCO ) contributed to TICE in mouse explants; TICE was highly responsive to changes in temperature and medium oxygenation. LDL-derived TICE was decreased by 58% (p<0.05) in explants from LDLR knockout mice (LDLR KO), compared with control C57Bl6J. In vivo free3H- or 3HCO-LDL-derived-TICE was conserved in LDLRKO mice, suggestive of a compensatory mechanism. LDL-derived TICE was increased by 62% (p<0.01) in PCSK9KO that present with ∼300% more intestinal LDLR. Acute depletion of intestinal LDLR with purified recombinant PCSK9 (i.v.) led to 40% (p<0.05) less TICE in PCSK9KO but had no effect in LDLRKO, confirming the implication of this receptor. Lovastatin (0.02% W/W 10d) increased TICE by 71% (p < 0.05) in C57Bl6J but not in LDLRKO. Interestingly, using 3H-cholesterol diluted in intralipid as a source, we showed that ABCB1 plays an important role in TICE. Indeed ABCB1ab -/- mice presented with 26% (p<0.05) less TICE than FVB controls in vivo and ABCB1 inhibitor PSC-833 (5mircoM) decreased TICE by 64% in an ABCB1 dependent fashion in explants. Collectively, these results provide the first molecular understanding of TICE.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".