Liver X Receptor Alpha Deficiency Primes Retinal Degeneration, but Aging Drives Disease Severity

Liver X receptor alpha (LXRα) regulates serum cholesterol and lipoprotein levels under homeostatic conditions and in response to dietary fat. Previously, aged Lxrα^-/- mice fed a standard diet were shown to develop phenotypes resembling early age-related macular degeneration (AMD). Herein, the hypothesis tested was that introducing a high-fat, high-cholesterol (HFC) diet in young Lxrα^-/- mice could bypass aging and accelerate onset of AMD-like pathology. Young Lxrα^+/+ and Lxrα^-/- mice (2 to 3 months old) were fed either a standard diet or an HFC diet for up to 2 months. Retinal function and morphology were assessed by electroretinography and fundus/optical coherence tomography imaging, histopathology by transmission electron microscopy, and retinal markers by immunostaining. Young Lxrα^-/- mice fed an HFC diet exhibited impaired retinal function with reduced scotopic a- and b-waves, photopic b-waves, and c-waves. Although the retinal ultrastructure of control and HFC-fed Lxrα⁺/⁺ mice appeared normal, HFC-fed Lxrα^-/- mice showed retinal pigment epithelium thinning, disorganized basal infoldings, intracellular lipid droplets, thin basal laminar deposits, and Bruch membrane thickening enriched in apolipoprotein E. Increased microglia/macrophage infiltration in the retina and choroid suggested elevated local inflammation. Although an HFC diet accelerated AMD-like changes in young Lxrα^-/- mice, these lesions were less severe than those observed in aged Lxrα^-/- mice on a standard diet, indicating that aging remains the dominant driver of disease severity.