Myeloid ACAT1/SOAT1: a novel regulator of dyslipidemia and retinal neovascularization

Abstract

Pathological retinal neovascularization (RNV) is a major cause of vision loss and blindness during ischemic retinopathies. Our investigations in the mouse model of oxygen-induced retinopathy (OIR) demonstrate a novel mechanism of pathological RNV and neurovascular injury. We show that OIR-induced activation of macrophage/microglial cells, retinal inflammation, and pathological RNV are mediated by increases in cholesterol ester (CE) formation due to activation of the acyl-CoA: Cholesterol Acyltransferase 1/Sterol O-Acyltransferase 1 (ACAT1/SOAT1) enzyme.

Fig. 1. A simplified schematic representation of steps linking dyslipidemia with macrophage/microglia induced RNV.

1) Enhanced LDL-cholesterol uptake: Under hypoxic/ischemic conditions, macrophages/microglia show increased expression of LDL-receptor (LDLR) and increased internalization of LDL-cholesterol (LDL-C). 2) Activation of ACAT1/SOAT1: Hypoxic/ischemic conditions promote increased cholesterol uptake along with increased ACAT1/SOAT1 activity which increases CE formation. 3) ROS mediated oxidation of CE: Ischemia induces ROS formation, which leads to CE oxidation (Ox-CE) via activation of radical and nonradical modification pathways. 4) Induction of Inflammation signaling: Ox-CE can activate TREM1 through TLR4^,. TREM1 induces inflammation by activating the DAP12/Syk (spleen tyrosine kinase) signaling cascade. TREM1 inhibition decreases levels of inflammatory cytokines. 5) Release of proinflammatory cytokines: The nuclear factor-κB (NFκβ) signaling pathway is induced by TREM1, which leads to the production of proinflammatory cytokines such as IL6, IL1β, TNFα, MCSF^, 6) Retinal neovascularization: Activated macrophages/microglia play a key role in regulating angiogenesis and are critically involved in the pathogenesis of RNV. Created in BioRender. Zaidi, S. (2025) BioRender.com/c38e697.