Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium

Engel, Abbi; Wang, YeKai; Khuu, Thomas; Worrall, Emily; Manson, Megan A.; Lim, Robert W.; Knight, Kaitlen; Yanagida, Aya; Qi, Jian Hua; Ramakrishnan, Aravind; Weleber, Richard G.; Klein, Michael L.; Wilson, David J.; Anand‐Apte, Bela; Hurley, James B.; Du, Jianhai; Chao, Jennifer R.

doi:10.1016/j.exer.2021.108899

Cited by 13 publications

(34 citation statements)

References 38 publications

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“…Sorsby’s fundus dystrophy (SFD) is a severe inherited retinal disorder with clinical and histological characteristics that overlap with AMD. SFD patients have a thicker Bruch’s membrane, which accumulates large, lipid-rich sub-RPE deposits (15, 43). SFD is caused by mutations in an extracellular matrix metalloprotease inhibitor TIMP3 (44), but the relationship between lipid pathology and the TIMP3 mutations is unclear.…”

Section: Resultsmentioning

confidence: 99%

“…After 12 weeks we checked cell polarity by quantifying VEGF released from RPE to the apical and basal chambers. SFD RPE, like normal RPE, secretes more VEGF into the basal chamber (15), ( Fig. 5f ).…”

Section: Resultsmentioning

confidence: 99%

“…The generation and differentiation of normal and SFD iPSC-RPE lines in this manuscript have previously been described (15, 30). Informed consent was obtained from all subjects (University of Washington IRB-approved STUDY00010851).…”

Section: Methodsmentioning

confidence: 99%

“…Diminished nutrient transport may contribute to photoreceptor degeneration in AMD (13). Soresby fundus dystrophy has a similar pathology as AMD, but with an earlier onset of symptoms (14, 15).…”

Section: Introductionmentioning

confidence: 99%

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Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux

Hass,

Pandey,

Engel

et al. 2023

Preprint

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PurposeIn age-related macular degeneration (AMD) and Sorsby’s fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE). Drusen may contribute to photoreceptor and RPE degeneration in AMD and SFD. We hypothesize that stimulating β-oxidation in RPE will reduce drusen accumulation. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, limits the accumulation of lipid deposits in cultured RPE cells.MethodsWe probed metabolism and cellular function in mouse RPE-choroid, human fetal- derived RPE cells, and induced pluripotent stem cell-derived RPE cells. We used13C6-glucose and13C16-palmitate to determine the effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism.13C labeling of metabolites in these pathways were analyzed using gas chromatography-linked mass spectrometry. We quantified ApoE and VEGF release using enzyme-linked immunosorbent assays. Immunostaining of sectioned RPE was used to visualize ApoE deposits. RPE function was assessed by measuring the trans-epithelial electrical resistance (TEER).ResultsACC inhibition with Firsocostat increases fatty acid oxidation and remodels lipid composition, glycolytic metabolism, lipoprotein release, and enhances TEER. When human serum is used to induce sub-RPE lipoprotein accumulation, fewer lipoproteins accumulate with Firsocostat. In a culture model of Sorsby’s fundus dystrophy, Firsocostat also stimulates fatty acid oxidation, improves morphology, and increases TEER.ConclusionsFirsocostat remodels intracellular metabolism and improves RPE resilience to serum-induced lipid deposition. This effect of ACC inhibition suggests that it could be an effective strategy for diminishing drusen accumulation in the eyes of patients with AMD.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux

Hass,

Pandey,

Engel

et al. 2023

Preprint

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“…Since our results suggests that mutant RPE do not display increased glutamine anaplerosis or proline synthesis, it is possible that the glutamine may be utilized for the biosynthesis of amino acids, nucleotides, and other macromolecules. Thickened Bruch’s membrane is a common pathological feature in patients with SFD 2,3,50 . It is possible that this is due to increased ECM biosynthesis because of increased glutamine.…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells

Grenell,

Singh,

Raju

et al. 2024

Preprint

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Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby’s Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. Quantitative proteomics and RNAseq analysis on the choroid/RPE of mice expressing mutant TIMP3 identified a dysregulation in metabolic processes. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. Stable isotope tracing experiments demonstrated enhanced glucose utilization and glycolytic activity in mutant RPE concomitantly with altered glutamine utilization. This study provides important information on the dysregulation of the metabolome of RPE cells in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

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Transcriptomic and Chromatin Accessibility Analysis of the Human Macular and Peripheral Retinal Pigment Epithelium at the Single-Cell Level

Mullin¹,

Voigt²,

Boese³

et al. 2023

The American Journal of Pathology

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Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium

Cited by 13 publications

References 38 publications

Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux

Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells

Transcriptomic and Chromatin Accessibility Analysis of the Human Macular and Peripheral Retinal Pigment Epithelium at the Single-Cell Level

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