Phagocytosis-dependent ketogenesis in retinal pigment epithelium
Open accessAbstract
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE, like the liver, expresses enzymes required for fatty acid oxidation and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS, as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of β-hydroxybutyrate (β-HB) in the apical medium following ingestion of OS by human fetal RPE and ARPE19 cells cultured on Transwell inserts. No increase in ketogenesis was observed following ingestion of oxidized OS or latex beads. Our studies further defined the connection between OS phagocytosis and ketogenesis in wild-type mice and mice with defects in phagosome maturation using a mouse RPE explant model. In explant studies, the levels of β-HB released were temporally correlated with OS phagocytic burst after light onset. In the Mreg −/− mouse where phagosome maturation is delayed, there was a temporal shift in the release of β-HB. An even more pronounced shift in maximal β-HB production was observed in the Abca4 −/− RPE, in which loss of the ATP-binding cassette A4 transporter results in defective phagosome processing and accumulation of lipid debris. These studies suggest that FAO and ketogenesis are key to supporting the metabolism of the RPE and preventing the accumulation of lipids that lead to oxidative stress and mitochondrial dysfunction.
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Phospholipases generate fatty acid substrates from ingested OS disk membrane phospholipids for mitochondrial β-oxidation.
“Phospholipases generate the fatty acid substrates from ingested OS disk membrane phospholipids for mitochondrial β-oxidation (see section 6) (Reyes-Reveles et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Reyes-Reveles et al., 2017
β-HB is preferentially transported across the apical membrane by MCT1.
“β-HB is preferentially transported across the apical membrane by MCT1 (Adijanto et al., 2014; Reyes-Reveles et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Reyes-Reveles et al., 2017
In Lc3b−/− and Mreg−/− mice, which display delayed phagosome maturation, there is a delay in β-HB production.
“In Lc3b−/− and Mreg−/− mice, that display delayed phagosome maturation, there was also a delay in β-HB production”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Reyes-Reveles et al., 2017
Fatty acid oxidation and ketogenesis are coupled to phagosome maturation processes.
“thus coupling FAO and ketogenesis to phagosome maturation processes (Reyes-Reveles et al., 2017; Dhingra et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Reyes-Reveles et al., 2017
Phagocytosed OS provide the RPE with fatty acids that are oxidized to provide substrate for ketogenesis.
“The protein- and lipid-rich phagocytosed OS provide the RPE with a metabolic bolus of fatty acids which are oxidized providing substrate for ketogenesis (Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
Loss of LAP results in dysregulated lipid metabolism.
“and dysregulated lipid metabolism (Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
The 50% decrease in β-HB is likely due to the reduced availability of free fatty acids from ingested OS phospholipids.
“Thus, we hypothesize that the 50% decrease in β-HB is likely due to the reduced availability of free fatty acids from ingested OS phospholipids (Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
The RPE has adapted LAP to eliminate stressors, including daily ingestion of lipids and proteins in OS tips.
“The RPE has adapted LAP to eliminate stressors, including the daily ingestion of lipids and proteins in the form of OS tips (Kim et al., 2013; Frost et al., 2015; Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
β-HB production due to slowed OS clearance is delayed in the LC3B-/- RPE, with maximal β-HB release seen 6 h after light onset, in contrast to WT, where maximal release is at 2 h after light onset.
“Herein we show that β-HB production due to slowed OS clearance is delayed in the LC3B-/- RPE, with maximal β-HB release seen 6 h after light onset, in contrast to WT, where maximal release is at 2 h after light onset (Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
Free fatty acids generated upon OS digestion serve as substrates for mitochondrial FAO and ketogenesis.
“Free fatty acids generated upon OS digestion serve as substrates for mitochondrial FAO and ketogenesis (Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Reyes-Reveles et al., 2017
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References 49 · Cited by 116
- Authors
- Reyes-Reveles, J., Dhingra, A., Alexander, D., Bragin, A., Philp, N. J., & Boesze-Battaglia, K.
- Affiliations
- University of Pennsylvania (US)
- Thomas Jefferson University (US)
- Corresponding author
- Philp, Nancy J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 292
- Issue
- 19
- Pages
- 8038-8047
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5427279
- OpenAlex
- W2595778161
- Cited by
- 116
- References
- 49
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 18 · 2023: 16 · 2022: 9 · 2021: 19 · 2020: 13 · 2019: 7 · 2018: 10 · 2017: 2
- FWCI
- 8.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ScholarlyCommons (University of Pennsylvania) (submittedVersion)
- Scholarly Commons (University of Pennsylvania) (submittedVersion)
- Funders
- National Institutes of Health (EY010420, EY012042, EY026525)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- retinal pigment epithelium, phagocytosis, photoreceptor outer segments, ketogenesis, fatty acid oxidation, beta-hydroxybutyrate, phagosome maturation, ABCA4, lipid recycling, oxidative stress, mitochondrial dysfunction
- MeSH terms
- Animals, Cell Line, Culture Media, Female, Genotype, Humans, Ketones, Lipids, Male, Mice, Inbred C57BL, Mitochondria, Oxygen, Phagocytosis, Phagosomes, Mice, Knockout, Oxidative Stress, Microscopy, Confocal, 3-Hydroxybutyric Acid, Mice, Retinal Pigment Epithelium
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