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Studies of ApoD−/− and ApoD−/−ApoE−/− mice uncover the APOD significance for retinal metabolism, function, and status of chorioretinal blood vessels

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Abstract

Apolipoprotein D (APOD) is an atypical apolipoprotein with unknown significance for retinal structure and function. Conversely, apolipoprotein E (APOE) is a typical apolipoprotein with established roles in retinal cholesterol transport. Herein, we immunolocalized APOD to the photoreceptor inner segments and conducted ophthalmic characterizations of ApoD−/− and ApoD−/−ApoE−/− mice. ApoD−/− mice had normal levels of retinal sterols but changes in the chorioretinal blood vessels and impaired retinal function. The whole-body glucose disposal was impaired in this genotype but the retinal glucose metabolism was unchanged. ApoD−/−ApoE−/− mice had altered sterol profile in the retina but apparently normal chorioretinal vasculature and function. The whole-body glucose disposal and retinal glucose utilization were enhanced in this genotype. OB-Rb, both leptin and APOD receptor, was found to be expressed in the photoreceptor inner segments and was at increased abundance in the ApoD−/− and ApoD−/−ApoE−/− retinas. Retinal levels of Glut4 and Cd36, the glucose transporter and scavenger receptor, respectively, were increased as well, thus linking APOD to retinal glucose and fatty acid metabolism and suggesting the APOD-OB-Rb-GLUT4/CD36 axis. In vivo isotopic labeling, transmission electron microscopy, and retinal proteomics provided additional insights into the mechanism underlying the retinal phenotypes of ApoD−/− and ApoD−/−ApoE−/− mice. Collectively, our data suggest that the APOD roles in the retina are context specific and could determine retinal glucose fluxes into different pathways. APOD and APOE do not play redundant, complementary or opposing roles in the retina, rather their interplay is more complex and reflects retinal responses elicited by lack of these apolipoproteins.

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Abbreviations

APOE:

Apolipoprotein E

APOD:

Apolipoprotein D

AQ4:

Aquaporin 4

ERG:

Electroretinographic recordings

FA:

Fluorescein angiography

FI:

Fundus imaging

GC–MS:

Gas chromatography–mass spectroscopy

HFHS:

High-fat high-sugar diet

IS:

Photoreceptor inner segments

NGS:

Normal goat serum

PBS:

Phosphate buffer saline

RPE:

Retinal pigment epithelium

SD-OCT:

Spectral-domain optical coherence tomography

TCA:

The tricarboxylic acid cycle

TEM:

Transmission electron microscopy

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Acknowledgements

This work was supported in part by NIH grants EY018383 and EY011373 (I.A.P.) and the unrestricted grant from Research to Prevent Blindness. Irina A. Pikuleva is a Carl F. Asseff Professor of Ophthalmology. The authors thank the Visual Sciences Research Center Core Facilities (supported by National Institutes of Health Grant P30 EY11373) for assistance with mouse breeding (Heather Butler and Kathryn Franke), animal genotyping (John Denker), tissue sectioning (Catherine Doller), and microscopy (Scott Howell and Anthony Gardella). We are also grateful to Dr. Hisashi Fujioka (Electron Microscopy Core facility) for help with studies of retinal ultrastructure, to Danie Schlatzer (Proteomics and Small Molecule Mass Spectrometry Core) for conducting retinal label free analysis, and to Dr. Neal Peachey for assistance with the ERG studies.

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA

    Nicole El-Darzi, Natalia Mast, Alexey M. Petrov, Tung Dao, Artem A. Astafev, Aicha Saadane & Irina A. Pikuleva

  2. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    Erin Prendergast, Emmy Schwarz & Ilya Bederman

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Contributions

IAP and AMP conception and study design; IAP study supervision; NED, NM, AMP, TD, AAA, AS, EP, ES, and IB produced and analyzed data; IAP, NM, AMP, and IB wrote and edited the manuscript.

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Correspondence to Irina A. Pikuleva.

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El-Darzi, N., Mast, N., Petrov, A.M. et al. Studies of ApoD−/− and ApoD−/−ApoE−/− mice uncover the APOD significance for retinal metabolism, function, and status of chorioretinal blood vessels. Cell. Mol. Life Sci. 78, 963–983 (2021). https://doi.org/10.1007/s00018-020-03546-3

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