Role of acyl-coenzyme A: cholesterol transferase 1 (ACAT1) in retinal neovascularization

Abstract

Background We have investigated the efficacy of a new strategy to limit pathological retinal neovascularization (RNV) during ischemic retinopathy by targeting the cholesterol metabolizing enzyme acyl-coenzyme A: cholesterol transferase 1 (ACAT1). Dyslipidemia and cholesterol accumulation have been strongly implicated in promoting subretinal NV. However, little is known about the role of cholesterol metabolism in RNV. Here, we tested the effects of inhibiting ACAT1 on pathological RNV in the mouse model of oxygen-induced retinopathy (OIR). Methods In vivo studies used knockout mice that lack the receptor for LDL cholesterol (LDLR−/−) and wild-type mice. The wild-type mice were treated with a specific inhibitor of ACAT1, K604 (10 mg/kg, i.p) or vehicle (PBS) during OIR. In vitro studies used human microglia exposed to oxygen–glucose deprivation (OGD) and treated with the ACAT1 inhibitor (1 μM) or PBS. Results Analysis of OIR retinas showed that increased expression of inflammatory mediators and pathological RNV were associated with significant increases in expression of the LDLR, increased accumulation of neutral lipids, and formation of toxic levels of cholesterol ester (CE). Deletion of the LDLR completely blocked OIR-induced RNV and significantly reduced the AVA. The OIR-induced increase in CE formation was accompanied by significant increases in expression of ACAT1, VEGF and inflammatory factors (TREM1 and MCSF) (p < 0.05). ACAT1 was co-localized with TREM1, MCSF, and macrophage/microglia makers (F4/80 and Iba1) in areas of RNV. Treatment with K604 prevented retinal accumulation of neutral lipids and CE formation, inhibited RNV, and decreased the AVA as compared to controls (p < 0.05). The treatment also blocked upregulation of LDLR, ACAT1, TREM1, MCSF, and inflammatory cytokines but did not alter VEGF expression. K604 treatment of microglia cells also blocked the effects of OGD in increasing expression of ACAT1, TREM1, and MCSF without altering VEGF expression. Conclusions OIR-induced RNV is closely associated with increases in lipid accumulation and CE formation along with increased expression of LDLR, ACAT1, TREM1, and MCSF. Inhibiting ACAT1 blocked these effects and limited RNV independently of alterations in VEGF expression. This pathway offers a novel strategy to limit vascular injury during ischemic retinopathy. Graphical Abstract

ACAT1 suppresses clear cell renal cell carcinoma progression by AMPK mediated fatty acid metabolism

“…Bioinformatic analysis identified the prognostic significance of ACAT1 in ccRCC, with patients exhibiting high ACAT1 expression levels demonstrating a more favorable prognosis than those with low ACAT1 expression. The complex biological processes governing tumor cell invasion and metastasis were emphasized, highlighting the crucial role of the equilibrium between cell proliferation and apoptosis in tumor development [ [19] , [20] ].…”

Aberrant lipid accumulation and retinal pigmental epithelium dysfunction in PRCD-deficient mice

“…Reduced rod OS DHA levels reported in canine Prcd C2Y/C2Y models (21) imply a higher-than-normal degree of disc saturation which can both retain and accumulate rod OS membrane cholesterol. It is well known that excessive retinal cholesterol in the photoreceptor OS is esterified (55–57). Our untargeted lipidomic analyses of retinal tissue shows accumulation of C.Es in addition to decreased DHA levels in Prcd -/- mice.…”

Epithelial Membrane Protein 2 (EMP2) Blockade Attenuates Pathological Neovascularization in Murine Oxygen-Induced Retinopathy

“… 39 Acyl-coenzyme A:cholesterol transferase 1 ( Acat1 ), a cholesterol-metabolizing enzyme, is upregulated in microglia in the OIR model, and treatment with the ACAT1 inhibitor, K604, inhibited retinal neovascularization. 40 ECH1, an enzyme involved in fatty acid oxidation, was identified as an activator of NV using a proteomics approach in the murine OIR model and validated as highly up-regulated in hypoxic human retinal endothelial cells. 41 However, our findings that EMP2 blockade increases Acat1 and Ech1 expression, not decreases them, may contribute to the incomplete attenuation of neovascularization observed in our study.…”