Effects of Cholesterol Metabolism on Corneal Endothelial Dysfunction in Patients With Type 1 Diabetes.

PURPOSE: Corneal endothelial dysfunction (CED) in patients with diabetes increases the risk of blindness following intraocular surgery. This study aimed to reveal how diabetes induces CED from the perspective of cholesterol metabolism. METHODS: Streptozotocin-induced type 1 diabetic mice and high glucose-cultured B4G12 cells were used as in vivo and in vitro models of diabetes, respectively. Human and mouse corneal endothelium samples were sent for single-cell RNA (scRNA-seq) and RNA sequencing (RNA-seq), respectively. Expression of genes related to cholesterol metabolism and function in corneal endothelial cells (CECs) was detected via RT-qPCR, Western blotting, and immunofluorescence staining. The cholesterol content was detected via filipin. The relationship between cholesterol metabolism and functional genes in CECs was confirmed by SREBF2/SQLE knockdown and cholesterol intervention. The protective effect of cholesterol in vivo was confirmed by anterior segment photography, optical coherence tomography, and Alizarin red staining in the anterior chamber of a model of diabetic mice. RESULTS: Diabetes disrupted the morphology of CECs and promoted corneal edema after intraocular surgery. High glucose conditions downregulated cholesterol biosynthesis and functional genes in CECs. The si-SREBF2, si-SQLE, and cholesterol depletion significantly impaired CEC function. The si-SREBF2 downregulated SQLE, whereas si-SQLE did not significantly affect SREBF2. Supplementation with cholesterol relieved the effect of high glucose on functional gene expression in CECs. Moreover, supplementation with cholesterol relieved corneal edema, reduced corneal thickness, and alleviated shape changes of the anterior chamber in diabetic mice. CONCLUSIONS: Diabetes induced CED by inhibiting SREBF2/SQLE-dependent cholesterol biosynthesis, suggesting cholesterol supplementation protects CECs from damage caused by intraocular surgery in patients with diabetes.