| First Author | Saadane A | Year | 2019 |
| Journal | Am J Pathol | Volume | 189 |
| Issue | 2 | Pages | 405-425 |
| PubMed ID | 30448403 | Mgi Jnum | J:270474 |
| Mgi Id | MGI:6276402 | Doi | 10.1016/j.ajpath.2018.10.013 |
| Citation | Saadane A, et al. (2019) Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in Cytochrome P450 46A1-Mediated Cholesterol Removal. Am J Pathol 189(2):405-425 |
| abstractText | 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 a 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 Lxralpha and Lxrbeta 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 retinal endothelial cells, and this expression was increased in the proinflammatory environment. Retinal Cyp46a1(-/-) phosphoproteome revealed altered phosphorylation of 30 different proteins, including tight junction protein zonula occludens 1 and aquaporin 4. Collectively, the data obtained establish metabolic and regulatory significance of CYP46A1 for the retina and suggest pharmacologic activation of CYP46A1 as a potential therapeutic approach to dyslipidemia-induced retinal damage. |
