June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Characterization of retinal architecture in a systemic HL/EL double knockout mouse model
Author Affiliations & Notes
  • Rohini M Nair
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ying Song
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Brent A Bell
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Kevin Zhang
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Daniel J Rader
    Departments of Genetics, Medicine, and Pediatrics, the Cardiovascular Institute, and the Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Joshua L Dunaief
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Venkata R M Chavali
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Rohini Nair None; Ying Song None; Brent Bell None; Kevin Zhang None; Daniel Rader None; Joshua Dunaief None; Venkata Chavali None
  • Footnotes
    Support  NEI/NIH grant 1R21EY028273-01A1, RPB Funds, BrightFocus Foundation Grant M2021007F
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 461. doi:
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      Rohini M Nair, Ying Song, Brent A Bell, Kevin Zhang, Daniel J Rader, Joshua L Dunaief, Venkata R M Chavali; Characterization of retinal architecture in a systemic HL/EL double knockout mouse model. Invest. Ophthalmol. Vis. Sci. 2022;63(7):461.

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

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Abstract

Purpose : Purpose: There have been several reports of impaired lipid metabolism in age-related macular degeneration (AMD) pathogenesis. Large-scale genome-wide association studies in AMD patients have identified genes, including LIPC (HL), CETP, APOE, and ABCA1, that play a role in the generation, transport, and metabolism of high-density lipoprotein (HDL) particles. Additionally, increased systemic lipid levels have been correlated with increased AMD risk, the exact role of which has not been explored. With the premise of dysregulated lipid metabolism as a risk factor for degenerative retinal disorders, our study aims to explore the age-related effect of systemic loss of two lipases, Hepatic Lipase (HL) and Endothelial Lipase (EL) on retinal ultrastructure and function.

Methods : The HL/EL DKO mice on a C57BL/6J background were aged for up to 14 months. Retinal structure and function were assessed using histology, electroretinography, and spectral-domain optical coherence tomography at 7 and 12 months. To investigate retinal pathology and lipid deposits with aging, histological and ultrastructural analysis were performed at 14 months in comparison to wild-type C57BL/6 mice.

Results : The HL/EL DKO mice showed a significant reduction, with age, in all the three-wave responses (rod-a, b, and cone-b) when compared to controls. Small punctate, hyperreflective foci were observed in the retinas of HL/EL DKO mice at 12 months. There was a significant reduction in the number of S-opsin expressing cones in the DKO mice when compared to the controls. Retinal expression of Glutamine Synthetase (mGS) and cellular retinaldehyde–binding protein (mCRALBP) was also found to be reduced in DKOs. The DKO mice showed a marked accumulation of neutral lipids and unesterified cholesterol droplets in the choroidal and sub-RPE region when stained using Oil Red O and BODIPY suggesting deregulated lipid clearance. Ultrastructural analysis of HL/EL DKO mice also showed multiple lipid droplets below the Bruch’s membrane (BrM). Additionally, we observed disrupted and swollen RPE basal infoldings in the DKO mice.

Conclusions : Systemic loss of HL and EL leads to degenerative retinal changes and accumulation of lipids in the RPE/BrM/choroid in aged HL/EL DKO mice, sharing features with AMD pathophysiology. Further studies are warranted to understand the role of dysregulated lipid metabolism in inducing age-related degenerative retinal changes.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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