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.
Highlights
Dysregulated lipid metabolism and inflammation are key contributors to the development of multiple diseases of aging, including the ocular neurodegenerative disease, age-related macular degeneration (AMD), a leading cause of blindness in the elderly in developed nations, which affects over 130 million people in toto [1, 2]
Given the critical role of advanced age in the development of AMD, we measured the relative expression of NR1H3 (LXRA) and NR1Η2 (LXRB) in human retinal pigment epithelial (RPE) cells isolated from donor tissue as a function of age (Figure 1, Supplemental Figure 1, and Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.131928DS1)
Given the role of liver X receptors (LXRs) in regulating lipid metabolism and inflammation, the 2 pathways associated with development of AMD, and our observation that LXR expression in human RPE cells decreases with age, we examined the visual function of aged LXR-knockout mice, after confirming that the absence of LXR globally affects LXR gene expression locally in the RPE-choroid (Supplemental Figure 7)
Summary
Dysregulated lipid metabolism and inflammation are key contributors to the development of multiple diseases of aging, including the ocular neurodegenerative disease, age-related macular degeneration (AMD), a leading cause of blindness in the elderly in developed nations, which affects over 130 million people in toto [1, 2]. The pathogenesis of early dry AMD remains to be fully understood, an array of risk factors have been identified, implicating disease-associated signaling pathways, most notably, age, along with environmental (e.g., smoking), and genetic factors (e.g., genes associated with inflammatory, complement, and lipid-regulating pathways) [6,7,8,9]. In spite of the wealth of accepted knowledge regarding potential risk factors, treatment options remain tenuous for patients suffering from the “early” dry form of AMD. There is a considerable need to identify critical signaling pathways that drive the initiation and progression of AMD and to develop appropriate animal models that could be used as a platform to test potential therapies and further discover disease-regulating pathways.
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