LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target
| Autor: | Ebraheim N. Ismail, Rajendra S. Apte, Steven Nusinowitz, James T. Handa, Jeffrey W. Ruberti, Peter Tontonoz, Faryan Tayyari, Goldis Malek, Michael E. Boulton, Mayur Choudhary, Pei-Li Yao, Roxana A. Radu |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Aging genetic structures Retinal Pigment Epithelium Neurodegenerative Inbred C57BL Mouse models Eye Mice Macular Degeneration 0302 clinical medicine 80 and over 2.1 Biological and endogenous factors Medicine Aetiology Liver X Receptors Aged 80 and over Mice Knockout General Medicine Middle Aged Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis Female lipids (amino acids peptides and proteins) medicine.symptom Research Article Adult Adolescent Knockout Inflammation Therapeutics Retina Proinflammatory cytokine Young Adult 03 medical and health sciences Downregulation and upregulation Animals Humans Retinopathy Liver X receptor Eye Disease and Disorders of Vision Aged Retinal pigment epithelium Animal business.industry Neurosciences Endothelial Cells Lipid metabolism Macular degeneration medicine.disease eye diseases Mice Inbred C57BL Disease Models Animal Ophthalmology 030104 developmental biology Nuclear receptor Disease Models Cancer research sense organs Transcriptome Digestive Diseases business Genome-Wide Association Study |
| Zdroj: | JCI insight, vol 5, iss 1 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.131928 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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