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Goldis Malek, Faryan Tayyari, Mayur Choudhary, Yiyi Wang, Zhichun Jiang, Steven Nusinowitz, Roxana A Radu, Peter Tontonoz; Liver x receptors (LXR) at the intersection of lipid metabolism and inflammation: implications for age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2016;57(12):5011.
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© ARVO (1962-2015); The Authors (2016-present)
LXRs are nuclear receptors that act as cholesterol sensors, not only controlling expression of genes associated with lipid metabolism but also inflammation. Due to the importance of lipid metabolism in AMD pathogenesis, we previously examined the LXR signaling pathway in AMD-vulnerable cells including retinal pigment epithelial (RPE) and choroidal endothelial cells, and found their activation alters the expression of lipid metabolic genes. Here we evaluated the effect of LXR activation on the expression of inflammatory markers and characterized the incidence and extent of LXR driven AMD-like ocular pathologies in aged transgenic mice.
Expression of inflammatory genes including IL-6, iNOS, COX2, IL-1β, IL-18, IL-27, IFN-γ, and MCP-1, was determined in human RPE and macaque choroidal endothelial cells following treatment with LXR agonists, antagonists and LXR alpha (α) or beta (β) siRNAs, by qPCR. Visual function and in vivo morphology of aged LXR α, β, αβ knockout mice were evaluated with electroretinography (ERGs) and optical coherence tomography (OCT). Post-mortem morphological evaluation of retinal sections was performed via electron and light microscopy. The presence of lipids and immune cells were evaluated in sections stained with oil red o or probed with antibodies to microglial and macrophage markers, respectively.
LXR activation repressed expression of inflammatory genes including MCP-1, iNOS, COX2, IL-1b and IL-6. Both scotopic and photopic ERG recordings in aged LXR-/- (αβ>α>β) demonstrated decreased amplitudes, compared to age-matched wildtype mice. Morphological evaluation, visualized by OCT and in post-mortem retinal sections, showed thick layers of lipid-rich sub-RPE deposits in LXR-/- mice (αβ and α). LXR β-/- also develop deposits but were relatively thinner and fewer than those observed in LXR αβ and α knockout mice. A significantly higher number of Iba+ cells were seen in αβ and α knockout mouse eyes compared to controls.
Previously we identified LXRs as regulators of RPE lipid metabolism signaling. Here we find LXRs also impact inflammation. We also find the absence of LXRs in mice results in phenotypic features of dry AMD. These mice may serve as a model to further understand the pathobiology of lipid-rich sub-RPE deposit formation or as a platform to test therapies targeting deposits.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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