LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target
Mayur Choudhary, … , Peter Tontonoz, Goldis Malek
Mayur Choudhary, … , Peter Tontonoz, Goldis Malek
Published December 12, 2019
Citation Information: JCI Insight. 2020;5(1):e131928. https://doi.org/10.1172/jci.insight.131928.
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Research Article Ophthalmology Therapeutics

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

Abstract

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.

Authors

Mayur Choudhary, Ebraheim N. Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A. Radu, Steven Nusinowitz, Michael E. Boulton, Rajendra S. Apte, Jeffrey W. Ruberti, James T. Handa, Peter Tontonoz, Goldis Malek

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Figure 1

NR1H3 expression in RPE declines with age.

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NR1H3 expression in RPE declines with age. (A) Expression of NR1H3 in R...
(A) Expression of NR1H3 in RPE cells isolated postmortem from donors, 18–94 years old; fold change relative to ARPE19; n = 31. Pearson’s R2 was calculated, P < 0.0001. (B) Expression of NR1H3 in RPE cells isolated postmortem from donors, 60–94 years old; fold change relative to ARPE19, n = 25. Pearson’s R2 was calculated; P = 0.018. (C) Agarose gel image of genomic DNA amplification products of NR1H3, NR1H2, and their obligate binding partners retinoid X receptors A and B (RXRA and RXRB) in retina, freshly isolated human RPE cells (fRPE), ARPE19 cells, primary human RPE cells (hRPE), human choroid, and RF/6A cells. β-Actin (ACTB) was used a loading control. Representative images of NR1H3 (12HCLC) immunohistochemical (IHC) staining (dark gray) in retina/RPE/choroid complex from non-AMD (D and E; arrows point to a cone and RPE cells) and AMD (G and H) donors. Arrowheads point to dark gray NR1H3 staining within drusen. Inset: IgG control. Scale bars: 50 μm (D), 25 μm (E). (F and I) NR1H3 immunofluorescence (IF) staining in non-AMD and AMD donors. Arrowheads point to NR1H3 staining, red. Scale bar: 25 μm (F). NR1H2 IHC staining in retina/RPE/choroid complex from non-AMD (J and K) and AMD (M and N) donors (arrowheads point to dark gray NR1H2 staining within drusen). (L and O) NR1H2 IF staining in non-AMD and AMD donors (arrowheads point to NR1H2 staining within drusen, green). Total number of eyes probed with antibodies (n = 2–10 from age-matched non-AMD and AMD donors, respectively). IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OS, outer segments; RPE, retinal pigment epithelial cells.