Lipid-sensor FFAR1 curbs autophagy and mitochondrial respiration in murine retinal angiomatous proliferation
Bibliographic record
Abstract
Mechanisms driving pathological angiogenesis in neovascular age-related macular degeneration (nvAMD) remain ill-understood.In a murine model of retinal angiomatous proliferation (RAP), a common subtype of nvAMD, we show that excess triglyceride-derived fatty acids are sensed by FFAR1 (free fatty acid receptor 1) in photoreceptors.FFAR1 suppresses TFEB (transcription factor EB), a master regulator of macroautophagy/autophagy and lipid metabolism, contributing to photoreceptors' energy failure in murine RAP.The metabolic signature observed in murine RAP mimics that of human nvAMD vitreous.Improving autophagy and mitochondrial respiration by deleting Ffar1 or using autophagy agonists reduces pathological RAP-like lesions.Our findings offer a putative mechanism by which elevated circulating triglyceride-derived fatty acids can dysregulate autophagy and energy homeostasis in photoreceptors and drive pathological angiogenesis.Neovascular AMD (nvAMD) is the leading cause of blindness in older adults.Retinal angiomatous proliferation (RAP) accounts for 12-15% of nvAMD and is a significant cause of blindness.In RAP, aberrant neovessels originate from the inner retina and invade photoreceptors disrupting vision.We previously showed that nutrient-starved photoreceptors drive pathological angiogenesis in a murine RAP model to reinstate retinal energy homeostasis.Metabolically active cells, such as photoreceptors, rely partly on autophagy to palliate nutrient scarcity.We, therefore, explored the hypothesis that autophagy can help rescue the energy crisis of photoreceptors in a murine RAP model and how autophagy might be dysregulated in that disease.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 0.000 |
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 teacher head, 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".