Novel Role of AcylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) in Diabetic Retinopathy

Abstract

Hypercholesterolemia and excessive cholesterol ester (CE) production have been linked to chronic inflammation and vascular dysfunction during cardiovascular disease. Upregulation of AcylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1), the enzyme responsible for retinal CE formation, has been implicated in pathological retinal neovascularization. Here we determine the role of this process in diabetic retinopathy (DR). Ins2Akita diabetic mice were treated with the specific ACAT1/SOAT1 inhibitor K604 (10 mg/Kg, i.p.) beginning at 10 weeks for 2 weeks or 8 months for 2 months. ACAT1/SOAT1 expression and CE formation were assayed along with oxidative stress, inflammation, vascular pathology, and neuronal function. ACAT1/SOAT1 expression was also assayed in human retinas and vitrectomy specimens. Retinas from early-stage Ins2Akita mice exhibited increases in CE deposition, superoxide production, and expression of ACAT1/SOAT1, LDLR, TREM1, MCSF, and VEGF along with leukostasis, vascular leakage, acellular capillary formation, retinal ganglion cell loss, and impaired visual function. Late-stage increases in CE, ACAT1/SOAT, oxidative stress, inflammation, and impaired visual function were also observed. These changes were significantly inhibited by K604 treatment. The protective effects were independent of changes in systemic glucose or body weight. Human retina and vitrectomy samples also showed increases in ACAT1/SOAT1 and CE, respectively. Specific inhibition of ACAT1/SOAT1 with K604 normalizes ACAT1/SOAT1 expression and CE formation and prevents increases in oxidative stress and inflammation and preserves retinal structure and function in both early and late stages of DR. These findings identify ACAT1/SOAT1 as a promising therapeutic target for both early intervention and later stage treatment of DR. One sentence summaryInhibiting cholesterol esterification limits retinal neurovascular injury in diabetes.