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
View: Text | PDF
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

×

Figure 6

NR1H3 regulates lipid deposition in the outer retina.

Options: View larger image (or click on image) Download as PowerPoint
NR1H3 regulates lipid deposition in the outer retina. Representative im...
Representative images from retina/RPE/choroid sections of 10- to 14-month-old (A) WT (n = 3), (B) Nr1h3–/– (n = 4), (C) Nr1h2–/– (n = 4), and (D) Nr1h3–/– Nr1h2–/– (n = 3) mice stained with Oil Red O to visualize neutral lipids are shown. Scale bar: 20 μm. Retina/RPE/choroid sections from 10- to 14-month-old (E) WT (n = 3) (F) Nr1h3–/– (n = 4) mice were stained for APOE (red) and EO6 (green). Representative images are shown. Scale bar: 20 μm. QFDE micrographs from 10- to 14-month-old (G and H) WT (n = 4) and (I, J, and L) Nr1h3–/– (n = 4) mice. In these micrographs, the fracture plan “hovers” between the RPE basal infoldings (BIs) and choriocapillaris (CC). (G) In the WT mouse, the BIs are located in the lower half and left side of the micrograph (BI, black border). The BI structure appears uniform and consistent. (I) In the Nr1h3–/– mouse, the BI region is located in the center of the micrograph and along the bottom edge (red border). Regions of the BI that have the unaffected structure (labeled BI, within black border), are predominantly adjacent to BrM, but most of the region in this micrograph shows a heavily disrupted BI (dBI). (H) Inset shows a higher magnification of a region that contains both healthy BI and BrM. (J) Inset shows the surface structure of the dBI and healthy BI. (K) Inset shows a high magnification of the dBI structure marked by the box in inset J. Scale bar: 4 μm (G and I), 1 μm (inset H and J), 250 nm (inset K). BrM, Bruch’s membrane; OCL, outer collagenous layer. (L) Representative image of healthy BrM from WT mouse, red dotted line; scale bar: 500 nm. (M) Representative image from Nr1h3–/– mouse, showing spherical particles in BrM, red dotted line and red arrowheads; scale bar: 500 nm. (N) A region of healthy BrM in the Nr1h3–/– mouse. Red dotted line; scale bar: 500 nm. Representative images of RPE autofluorescence from 10- to 14-month-old (O) WT, (P) Nr1h3–/–, (Q) Nr1h2–/–, and (R) Nr1h3–/– Nr1h2–/– mice. (S) Quantification of lipofuscin autofluorescence in RPE cells. n = 2 measurements in n = 5 eyes per genotype. Mean ± SEM shown. *P < 0.05, 1-way ANOVA, Dunnett’s multiple-comparisons test.