LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target
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
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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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 5

Pathology of Nr1h3–/– mice reveals isoform-specific differences.

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Pathology of Nr1h3–/– mice reveals isoform-specific differences. Micron ...
Micron IV–acquired in vivo images of the posterior poles of 10- to 14-month-old (A and B) WT (n = 4), (C and D) Nr1h3–/– (n = 5), (E and F) Nr1h2–/– (n = 3), and (G and H) Nr1h3–/– Nr1h2–/– (n = 4) mice. Black arrowheads point to hyporeflective spots in the fundus. Toluidine blue–stained images of plastic sections from (I) WT (n = 4), (J) Nr1h3–/– (n = 5), (K) Nr1h2–/– (n = 3), and (L) Nr1h3–/– Nr1h2–/– (n = 4) mice showed normal retinal morphology and no gene-specific differences at the level of the inner retina. Scale bar: 20 μM (I). Conventional electron micrographs of RPE/Bruch’s membrane/choroidal junction in (M and N) WT mice display normal RPE morphology, while (O and P) Nr1h3–/– mice illustrate continuous sub-RPE deposits (marked by red dotted line) and disorganized RPE basal infoldings. (Q and R) Nr1h2–/– mice develop sub-RPE deposits (marked by red dotted line) along with large lipid droplets (red arrowheads) within the RPE, while (S and T) Nr1h3–/– Nr1h2–/– mice display a more severe form of both pathologies. Sub-RPE deposits, red dotted line; lipid droplets, red arrowheads. cTEM scale bar: 1 μm. CC, choriocapillaris; OS, outer segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer.