June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
VLC-PUFA supplementation increases Elovanoid synthesis in a two-compartment Late-Onset Retinal Degeneration-iRPE model
Author Affiliations & Notes
  • Jeff Xiang Ji
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Jorgelina Muriel Calandria
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Megan Cothern
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Rasangi Perera
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Kapil Bharti
    Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, Maryland, United States
  • Kiyoharu Miyagishima
    Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, Maryland, United States
  • Ruchi Sharma
    Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, Maryland, United States
  • Nicolas G Bazan
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Footnotes
    Commercial Relationships   Jeff Ji None; Jorgelina Calandria None; Megan Cothern None; Rasangi Perera None; Kapil Bharti None; Kiyoharu Miyagishima None; Ruchi Sharma None; Nicolas Bazan None
  • Footnotes
    Support  NEI grant R01EY005121 (NGB), the EENT Foundation (NGB), and the Yvette C. Villere Chair for the Study of Retinal Degeneration (NGB)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 5456. doi:
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      Jeff Xiang Ji, Jorgelina Muriel Calandria, Megan Cothern, Rasangi Perera, Kapil Bharti, Kiyoharu Miyagishima, Ruchi Sharma, Nicolas G Bazan; VLC-PUFA supplementation increases Elovanoid synthesis in a two-compartment Late-Onset Retinal Degeneration-iRPE model. Invest. Ophthalmol. Vis. Sci. 2023;64(8):5456.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in Complement C1q Tumor Necrosis Factor-Related Protein 5 (CTRP5) causes autosomal dominant late-onset retinal degeneration (L-ORD). Previous studies have shown that in vitro models of L-ORD RPE display a dysregulation of AMPK, abnormal lipid metabolism, and reduced production of NPD1. In this study, we compared the production of Elovanoids (ELVs), a novel class of DHA-synthesized neuroprotective mediators, from VLC-PUFA precursors supplied from the apical or basal surface in human RPE cells derived from siblings with discordant CTRP5 allele.

Methods : In vitro L-ORD-iRPE (induced pluripotent stem cell-derived RPE) disease model was developed from skin fibroblasts from two siblings with a p.Ser163Arg CTRP5 mutation while cells from two unaffected siblings were used to generate control iRPE. The cells were cultured in trans-well dishes containing an apical and basal chamber and exposed to ELV precursors VLC-PUFAs 32:6n3 and 34:6n3 added to the apical or basal compartment. Extracted lipids from the culture media were analyzed by LC-MS/MS.

Results : VLC-PUFAs introduced to the basal compartment show a greater levels of mono-hydroxylated 32:6n3/34:6n3 and ELV32/ELV34 in the apical compartment in L-ORD-iRPE compared to control while there was no significant change in ELV32/ELV34 or monohydroxylated precursors in the basal compartment between L-ORD-iRPE compared to control. Addition of VLC-PUFAs into the apical compartment produced no significant difference in monohydroxylated precursors or ELVs in the apical compartment between control and L-ORD-iRPE cells.

Conclusions : We found that supplementation with ELV precursors from the basal compartment of RPE from L-ORD patients led to greater levels of neuroprotective ELVs in the apical compartment compared to control RPE. The increase in ELVs in L-ORD-iRPE may reflect a compensatory increase in ELVs synthesis after supplementation with ELV precursor that are normally unavailable to CTRP5 mutants. This is consistent with previous findings that DHA, the precursor to VLC-PUFAs, is lower in the apical media in CTRP5 mutant L-ORD iRPE. The reduction in DHA could be explained by the disrupted function of ADIPOR1, a binding partner of CTRP5. Future studies will investigate the lipidomic profile of VLC-PUFAs and protection by ELVs against retinal degeneration in L-ORD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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