Novel Role of AcylCoA: Cholesterol Acyltransferase 1/Sterol O-Acyltransferase 1 (ACAT1/SOAT1) in Diabetic Retinopathy

Purpose: Hypercholesterolemia has been linked to inflammation and vascular dysfunction in diabetic retinopathy (DR). Excessive cholesterol ester (CE) production in macrophages can induce increases in inflammatory and angiogenic cytokines. AcylCoA:cholesterol acyltransferase 1/Sterol O-acyltransferase 1 (ACAT1/SOAT1) is responsible for cholesterol esterification. Here we determine its role in diabetic retinopathy (DR). We hypothesized that DR-induced increases in ACAT1/SOAT1-mediated CE formation triggers retinal inflammation and injury. Methods: Ins2Akita mice were treated with the ACAT1/SOAT1 inhibitor K604 (10 mg/kg, intraperitoneally) from 10 to 12 weeks or eight to 10 months. Plasma and retinal CE, oxidative stress, inflammation, vascular pathology, and retinal function were assessed by ELISA, qPCR, Western blot, leukostasis and permeability assays, electroretinography (ERG), and OptoMotry. ACAT1/SOAT1 expression and CE levels were assayed in retinal sections and vitreous samples from DR donors. Results: Retinas from 12-week-old Ins2Akita mice exhibited increases in CE and superoxide, and expression of ACAT1/SOAT1, LDLR, TREM1, MCSF, and VEGF along with leukostasis, hyperpermeability, acellular capillaries, retinal ganglion cell loss, and impaired ERG and visual acuity function. K604 treatment inhibited these changes. Retinas from 10-month-old Ins2Akita mice also showed increased ACAT1/SOAT1, LDLR, TREM1, MCSF, CE, superoxide, hyperpermeability, and impaired ERG and acuity responses that were inhibited by K604. These protective effects were independent of changes in systemic glucose or body weight. Conclusions: ACAT1/SOAT1 inhibition normalizes ACAT1/SOAT1 expression and CE formation, prevents oxidative stress and inflammation, and limits vascular and retinal dysfunction in both early- and late-stage DR. These findings identify ACAT1/SOAT1 as a promising target for treatment of DR.