Abstract 29: MiR-33 Coordinately Regulates Macrophage Autophagy
Bibliographic record
Abstract
Macrophage autophagy is thought to be essential for protecting from atherosclerosis, and compromised autophagy in macrophages of the artery wall leads to a number of pathologic processes including activation of the inflammasome, defective efferocytosis, and impaired cholesterol metabolism. Autophagy of lipid droplets (LDs) or “lipophagy” catabolizes stored lipids to maintain cellular energy homeostasis and plays a key role in cholesterol efflux by regulating LD-cholesterol mobilization, a rate-limiting step in macrophage reverse cholesterol transport (RCT). MicroRNA-33 (miR-33) is a well-established post-transcriptional RCT regulator, yet the complete mechanisms by which anti-miR33 exerts its beneficial effects on cholesterol metabolism are not known. Notably, microRNA target prediction algorithms identify a number of essential autophagy-related proteins (ATG5, ATG7) and lysosomal effectors (lysosomal-associated membrane protein 1 [LAMP1], lysosomal acid lipase [LAL]) as putative miR-33 targets. Quantitative PCR array profiling in mouse peritoneal macrophages revealed that a high proportion of autophagy genes are reciprocally regulated by miR-33 overexpression and inhibition. We validated a subset of genes in the autophagy pathway as bona fide miR-33 targets using 3′UTR luciferase assays and confirmed regulation of these targets by miR-33 using quantitative PCR and western blot analysis. Furthermore, we show that miR-33 indirectly regulates the expression of two master regulators of autophagy and lysosomal biogenesis gene programs: forkhead box O (FOXO) 3 and transcription factor EB (TFEB), via targeting of 5' AMP-activated protein kinase (AMPK). Inhibition of miR-33 in peritoneal macrophage in vitro enhanced cellular autophagic flux, as observed by fluorescence microscopy and western blot analysis, and autophagy was required for anti-miR33 promotion of cholesterol efflux. Furthermore, anti-miR33 treatment of atherosclerotic Ldlr-/- mice enhanced autophagy in plaque macrophages and triggered atherosclerosis regression. These data describe a novel role for miR-33 in the regulation of autophagy and identify additional mechanisms by which anti-miR33 therapy protects against atherosclerosis.
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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 | 0.000 |
| 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) | 0.003 | 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".