TY - JOUR
T1 - LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target
AU - Choudhary, Mayur
AU - Ismail, Ebraheim N.
AU - Yao, Pei Li
AU - Tayyari, Faryan
AU - Radu, Roxana A.
AU - Nusinowitz, Steven
AU - Boulton, Michael E.
AU - Apte, Rajendra S.
AU - Ruberti, Jeffrey W.
AU - Handa, James T.
AU - Tontonoz, Peter
AU - Malek, Goldis
N1 - Funding Information:
This research was supported by the National Eye Institute grants R01 EY027802 (GM), R01 EY028160 (GM), P30 EY005722 (to the Duke Eye Center), EY000331 (to the Stein Eye Institute, Core Grant for Vision Research), R01 EY019287-06 (RSA), P30 EY02687 (to Washington University, Core Grant for Vision Research), and R01 EY027691 (JTH, Robert Bond Welch Professor); the Edward N. & Della L. Thome Memorial Foundation Award (GM); the Carl and Mildred Almen Reeves Foundation (RSA); the Starr Foundation (RSA); the Bill and Emily Kuzma Family Gift for Retinal Research (RSA); the Jeffrey Fort Innovation Fund (RSA); the Glenn Foundation for Medical Research and the Thome Foundation (RSA); and the Research to Prevent Blindness, Inc, Core grant (to the Duke Eye Center). We are grateful to the donors and donor families for their generosity. We thank Neal Peachy for assistance with the c-wave recording protocols. Sincere thanks to Donald P. McDon-nell and Ching-Yi Chang for plasmids used in transcriptional activity assays and valuable discussions. We thank Abdoulaye Sene, Xiaoping Qi, Eddie Meade, and Michael Lekwuwa for technical support.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85080853335&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.131928
DO - 10.1172/jci.insight.131928
M3 - Article
C2 - 31829999
AN - SCOPUS:85080853335
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 1
M1 - e131928
ER -