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Faryan Tayyari, Mayur Choudhary, Peter Tontonoz, James T Handa, Goldis Malek; Evaluating the efficacy of treatment with an LXR agonist on the pathogenesis of early AMD. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1940.
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© ARVO (1962-2015); The Authors (2016-present)
Previously, we demonstrated that the Liver X Receptor (LXR) can regulate lipid metabolism and inflammation in the eye, similar to its reported functions in other endocrine organs. We found that aged LXR knockout mice develop several phenotypic features of dry AMD. Herein, we tested the therapeutic potential of LXR activation on removal of accumulated lipids in Bruch’s membrane and inflammatory cells within the retina, using the apoB100 transgenic mouse model.
Expression lipid metabolism (i.e. ABCA1, SREBP, apoE, FAS) and inflammatory (i.e. IL-6, IL-18, NF-kB, CFH, MCP-1, TGF-b, OPN, CD36) were investigated in human primary RPE (hRPE) cell lines (n=3 replicates) treated with LXR agonists (GW3965, TO901317), and an antagonist (GSK1440233A). ApoB100 mice, characterized by the accumulation of lipids within Bruch’s membrane (2 months of age; n=4-6, males and females) were fed either a low fat diet (LFD) or LFD enriched with an LXR agonist for 5 months. Wild-type (WT) and apoB100 mice on normal chow served as additional controls. Visual function and in vivo morphology were examined by electroretinography (ERG) and optical coherence tomography (OCT), respectively. Electron and light microscopy were used to quantify morphological changes (n=3 mice).
LXR activation in hRPE cells upregulated expression of lipid regulatory genes (SREBP, FAS, apoE) and repressed the expression of inflammatory genes (IL-6, NF-kB, TGF-b, OPN). Scotopic a-wave amplitudes decreased in apoB100 mice on normal diet compared to WT mice, which improved in mice on the LFD. No differences in ERG amplitudes were seen due to treatment with the LXR agonist. OCT, electron and light microscopy revealed a decrease in retinal pathology in apoB100 mice treated with the LXR agonist, including the presence of focal RPE degeneration and sub-RPE deposits. Finally, an increase in Iba+ and F4/80+ cells and GFAP immunoreactivity was seen in the retina of apoB100 mice compared to WT. Treatment with the LXR agonist resulted in a decrease in the number of retinal inflammatory cells, extent of GFAP staining, and apolipoprotein E accumulation in Bruch’s membrane in apoB100 mice.
The data support the hypothesis that LXR is an AMD regulatory signaling pathway and that its activation may be therapeutically beneficial in ameliorating pathologies associated with the disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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