Abstract
Purpose :
The liver x nuclear receptor α (LXRα) is a regulator of lipid metabolism and inflammation, pathways relevent to AMD development, the leading cause of vision loss in the elderly. Previously we reported that aged Lxrα–/– mice develop early ‘AMD’-like phenotypes. Herein we investigated if the addition of a dietary burden in Lxrα-/- mice may accelerate onset of disease.
Methods :
Two-month-old Lxrα–/– mice were fed either a regular (control; n=6) or high fat+cholesterol diet (HFC, n=6) for 12 weeks. Body weights were recorded (2X/week). Visual functions and in vivo morphology were assessed by electroretinography and fundus/OCT imaging, respectively, before and after diet regimen. Following euthanasia, body/organ weights were measured. Eyes were processed for transmission electron microscopy evaluation (TEM), cryopreserved, or snap frozen for protein or mRNA analysis. Histopathology was assessed in H&E stained frozen sections, toluidine blue stained plastic sections, and by TEM. Distribution of cell-specific markers in the retina were examined by immunostaining.
Results :
Non-alcoholic fatty liver was observed in HFC fed Lxrα–/– mice (n=6/6). Average liver and spleen weights were heavier in HFC fed mice compared to controls (4.5- and 2.6-fold, respectively). Serum cholesterol, HDL and LDL levels were significantly higher in HFC fed mice compared to controls (2.3-, 4.6- and 3.9-fold, respectively). Scotopic a-wave, scotopic b-wave, photopic b-wave and c-wave amplitudes of HFC fed mice were reduced by 73%, 84%, 50% and 50%, respectively, compared to controls. Increased APOE accumulation along Bruch’s membrane (BrM) in HFC fed mice was measured compared to controls (10.9-fold). Similarly, number of retinal Iba1+ cell in HFC fed mice was significantly greater than that of controls (1.5-fold). While the ultrastructure of the retina/RPE was normal by TEM in control diet fed mice, a thin and discontinuous RPE layer was observed in HFC fed mice, along with disorganized basal infoldings, thickening of BrM, and increased mitochondrial number (1.3-fold compared to controls).
Conclusions :
We find that in the absence of Lxrα, a fatty diet (1) causes liver damage and compromised immune system; (2) increases blood cholesterol contents; (3) facilitates the early onset of AMD-like phenotypes in mice; and (4) impairs impair visual function.
This is a 2020 ARVO Annual Meeting abstract.