Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in CYP46A1-Mediated Cholesterol Removal.

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in CYP46A1-Mediated Cholesterol Removal. Am J Pathol. 2018 Nov 15;: Authors: Saadane A, Mast N, Trichonas G, Chakraborty D, Hammer S, Busik JV, Grant MB, Pikuleva IA Abstract CYP46A1 is the cytochrome P450 enzyme that converts cholesterol to 24-hydroxycholesterol, a cholesterol elimination product and a potent liver X receptor (LXR) ligand. We conducted retinal characterizations of Cyp46a1-/- mice that had normal fasting blood glucose levels but up to 1.8-fold increase in retinal cholesterol. The retina of Cyp46a1-/- mice exhibited venous beading and tortuosity, microglia/macrophage activation, and increased vascular permeability, features commonly associated with diabetic retinopathy. The expression of Lxrα and Lxrβ was increased in both the whole Cyp46a1-/- retina and retinal macroglia/macrophages. The LXR-target genes were affected as well, primarily in activated microglial cells and macrophages. In the latter, the LXR-transactivated genes (Abca1, Abcg1, Apod, Apoe, Mylip, and Arg2) were up-regulated; similarly, there was an up-regulation of the LXR-transrepressed genes (Ccl2, Ptgs2, Cxcl1, Il1b, Il6, Nos2, and Tnfa). For comparison, gene expression was investigated in bone marrow-derived macrophages from Cyp46a1-/- mice as well as retinal and bone marrow-derived macrophages from Cyp27a1-/- and Cyp27a1-/-Cyp46a1-/- mice. CYP46A1 expression was detected in retina...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research

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