髓样ACAT1/SOAT1：一种新的血脂异常和视网膜新生血管的调节因子-动脉网

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

Nature 等信源发布 2025-01-13 21:12

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Abstract

摘要

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..

病理性视网膜新血管形成（RNV）是缺血性视网膜病变期间视力丧失和失明的主要原因。我们在氧诱导视网膜病变（OIR）小鼠模型中的研究证明了病理性RNV和神经血管损伤的新机制。我们表明，OIR诱导的巨噬细胞/小胶质细胞活化，视网膜炎症和病理性RNV是由酰基辅酶A：胆固醇酰基转移酶1/固醇O-酰基转移酶1（ACAT1/SOAT1）酶激活引起的胆固醇酯（CE）形成增加介导的。。

Introduction

简介

Ischemic retinopathies, including diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion, are common causes of vision loss and blindness in developed countries worldwide

缺血性视网膜病变，包括糖尿病视网膜病变、早产儿视网膜病变和视网膜静脉阻塞，是全世界发达国家视力丧失和失明的常见原因

. Conventional therapies include repeated intravitreal injections of anti-VEGF (vascular endothelial growth factor), steroids, vitrectomy, or photocoagulation. All are associated with some risk of damaging side effects, including inflammation, retinal detachment, endophthalmitis, and vitreous hemorrhage.

常规疗法包括反复玻璃体内注射抗VEGF（血管内皮生长因子），类固醇，玻璃体切除术或光凝术。所有这些都与一些破坏性副作用的风险有关，包括炎症，视网膜脱离，眼内炎和玻璃体出血。

Rapid vascular regrowth may occur upon interruption of the VEGF blockade and its effectiveness is limited in some patients.

VEGF阻断中断后可能会发生快速血管再生，其有效性在某些患者中受到限制。

. Steroid injections can induce increases in intraocular pressure or cataract formation and vitrectomy or photocoagulation can damage healthy cells. These limitations underscore the need for additional effective treatments that reverse RNV and promote physiological repair while avoiding the side effects of current therapeutic options..

类固醇注射可引起眼内压升高或白内障形成，玻璃体切除术或光凝术可损害健康细胞。这些局限性强调了需要额外的有效治疗，以逆转RNV并促进生理修复，同时避免当前治疗选择的副作用。。

In ischemic retinopathies hypoxia, oxidative stress, and inflammation are key factors underlying the retinal damage

. Activation of microglia and macrophages also plays a key role in ischemic retinopathy and both cell types are critically involved in the pathogenesis of pathological RNV

小胶质细胞和巨噬细胞的激活在缺血性视网膜病变中也起着关键作用，这两种细胞类型都与病理性RNV的发病机制密切相关

. Although these factors are all connected, the order of these events and their underlying mechanisms have not been well demonstrated. In this perspective review we will focus on the role of the cholesterol metabolizing enzyme ACAT1/SOAT1 and CE formation in retinal inflammation and pathological RNV in the mouse model of oxygen-induced retinopathy (OIR)..

尽管这些因素都是相互关联的，但这些事件的顺序及其潜在机制尚未得到很好的证明。在这篇综述中，我们将重点关注胆固醇代谢酶ACAT1/SOAT1和CE形成在氧诱导视网膜病变（OIR）小鼠模型中视网膜炎症和病理性RNV中的作用。。

While dyslipidemia and cholesterol accumulation have been strongly implicated in promoting pathological NV in models of subretinal NV

虽然在视网膜下NV模型中，血脂异常和胆固醇积累与促进病理性NV密切相关

, not much is known about role of cholesterol metabolism, activation of ACAT1/SOAT1, and CE formation in pathological RNV during ischemic retinopathy. More is known about the involvement of the ACAT1/SOAT1 pathway in other diseases. Increased ACAT1/SOAT1 expression/activity in activated macrophages has been implicated in atherosclerosis, Alzheimer’s disease, and cancer.

，关于缺血性视网膜病变期间胆固醇代谢，ACAT1/SOAT1激活和CE形成在病理性RNV中的作用知之甚少。关于ACAT1/SOAT1途径参与其他疾病的了解更多。。

. Epidemiological studies and clinical trials have shown a correlation between high levels of plasma cholesterol and diabetic retinopathy

流行病学研究和临床试验表明，高水平的血浆胆固醇与糖尿病视网膜病变之间存在相关性

. Alterations in cholesterol metabolism have also been shown to induce cholesterol accumulation and formation of hyperreflective cholesterol crystals that impair visual function in the diabetic retina

胆固醇代谢的改变也被证明会诱导胆固醇积累和形成高反射性胆固醇晶体，从而损害糖尿病视网膜的视觉功能

Oxidative/nitrative stress, macrophage activation, inflammation, and pathological RNV

氧化/硝化应激，巨噬细胞活化，炎症和病理性RNV

The mouse model of OIR has served as a key experimental tool for elucidating the mechanisms of pathological RNV. In this model, neonatal mice are maintained in hyperoxia from postnatal day 7 (P7) to P12, the time when the retinal vessels are forming, and then returned to normoxia. The hyperoxia environment induces obliteration of the immature vessels and prevents further microvascular development.

OIR的小鼠模型已成为阐明病理性RNV机制的关键实验工具。。高氧环境诱导未成熟血管闭塞并阻止进一步的微血管发育。

Because the retinal neurons continue to develop normally during the hyperoxia treatment, the lack of the normal blood supply to the retinal tissue leads to relative hypoxia and promotes pathological vitreoretinal NV when the neonates are returned to normoxia on P12..

由于视网膜神经元在高氧治疗期间继续正常发育，因此当新生儿在P12恢复常氧时，视网膜组织缺乏正常血液供应会导致相对缺氧并促进病理性玻璃体视网膜NV。。

In models of OIR in vivo and hyperoxia-treated endothelial cells in vitro, oxidative/nitrative stress has been shown to play a key role in the hyperoxia-induced endothelial cell death

在体内OIR和体外高氧处理的内皮细胞模型中，氧化/硝化应激已被证明在高氧诱导的内皮细胞死亡中起关键作用

. There are several sources of oxidative/nitrative stress in the OIR model, including superoxide and peroxynitrite

. Superoxide formation due to activation of the NADPH oxidase NOX2 isoform together with nitric oxide formation due to increased expression of inducible nitric oxide synthase (iNOS) have been strongly implicated in retinal vascular injury during OIR and other models of ischemic retinopathy, including diabetic retinopathy and ischemia-reperfusion injury.

在OIR和其他缺血性视网膜病变模型（包括糖尿病视网膜病变）期间，由于NADPH氧化酶NOX2亚型的激活以及由于诱导型一氧化氮合酶（iNOS）表达增加而形成的一氧化氮，导致的超氧化物形成与视网膜血管损伤密切相关。缺血再灌注损伤。

. Superoxide and nitric oxide react to form the toxic product peroxynitrite, which damages the retinal cells as well as reducing the availability of nitric oxide needed for normal vascular and neuronal function

.超氧化物和一氧化氮反应形成有毒产物过氧亚硝酸盐，这会损害视网膜细胞，并降低正常血管和神经元功能所需的一氧化氮的可用性

Protein synthesis pathways in the endoplasmic reticulum, Golgi apparatus, and nucleus as well as protein turnover pathways are all highly sensitive to ROS-related redox conditions

内质网、高尔基体和细胞核中的蛋白质合成途径以及蛋白质周转途径都对活性氧相关的氧化还原条件高度敏感

. Long chain unesterified free fatty acids along with some of their derivatives and metabolites can modify intracellular production of ROS

长链未酯化的游离脂肪酸及其一些衍生物和代谢物可以改变细胞内ROS的产生

. Also, oxidative and nitrative stress mediate the activation of proinflammatory signaling pathways and promote induction of the M1-like proinflammatory macrophages during OIR

此外，氧化和硝化应激介导促炎信号通路的激活，并促进OIR期间M1样促炎巨噬细胞的诱导

Studies in the OIR model have shown a key role of macrophage activation in this pathology. Depletion of macrophages during the relative hypoxia/RNV phase by intraperitoneal injections of clodronate-liposomes reduced retinal macrophage numbers by approximately 80% and significantly inhibited pathological RNV while improving physiological vascular repair.

OIR模型的研究表明巨噬细胞活化在这种病理中起着关键作用。通过腹膜内注射氯膦酸盐脂质体在相对缺氧/RNV期消耗巨噬细胞使视网膜巨噬细胞数量减少约80%，并显着抑制病理性RNV，同时改善生理性血管修复。

. In contrast, macrophage depletion during the hyperoxia phase did not affect the vaso-obliteration. These findings demonstrated that macrophage depletion markedly decreased OIR severity as well as reducing levels of angiogenic cytokines and extracellular matrix degradation

相反，高氧期巨噬细胞耗竭不影响血管闭塞。这些发现表明，巨噬细胞耗竭显着降低了OIR的严重程度，并降低了血管生成细胞因子和细胞外基质降解的水平

. Studies in the OIR model also have reported a population of M1-like proinflammatory microglia/macrophages localized to the areas of pathological RNV during the relative hypoxia/RNV phase along with activation of the NFκβ / STAT3 signaling pathway and increased expression of inflammatory cytokines including TNFα, IL6, and IL1β.

OIR模型的研究还报道了在相对缺氧/RNV期，M1样促炎性小胶质细胞/巨噬细胞群体定位于病理性RNV区域，同时激活NFκβ/STAT3信号通路，增加炎性细胞因子的表达，包括TNFα，IL6和IL1β。

In the OIR model, cells in the ischemic tissue promote pathological RNV by secreting VEGF and other angiogenic factors along with macrophage chemotactic protein 1 (MCP1), and macrophage colony stimulating factor (MCSF1)

在OIR模型中，缺血组织中的细胞通过分泌VEGF和其他血管生成因子以及巨噬细胞趋化蛋白1（MCP1）和巨噬细胞集落刺激因子（MCSF1）来促进病理性RNV

. MCP1

.MCP1

CCL2 is a member of the C-C chemokine family and a potent chemotactic factor that attracts macrophages into the retina where they can release pro-angiogenic factors, promoting the growth of abnormal blood vessels. Once the macrophages are recruited, MCSF1 further activates them, enhancing their ability to produce inflammatory mediators and contribute to pathological angiogenesis.

CCL2是C-C趋化因子家族的成员，是一种有效的趋化因子，可将巨噬细胞吸引到视网膜中，在那里它们可以释放促血管生成因子，促进异常血管的生长。一旦巨噬细胞被募集，MCSF1就会进一步激活它们，增强其产生炎症介质的能力并促进病理性血管生成。

. It has been shown that inhibition of MCP1 decreases RNV

研究表明，抑制MCP1可降低RNV

. MCSF1 secreted by macrophages, is required for the differentiation of resident macrophages and microglia during development

巨噬细胞分泌的MCSF1是发育过程中常驻巨噬细胞和小胶质细胞分化所必需的

. Inhibition of MCSF1 selectively suppresses tumor angiogenesis and in contrast to VEGF blockade, MCSF1 inhibition does not promote rapid vascular regrowth

抑制MCSF1选择性地抑制肿瘤血管生成，与VEGF阻断相反，MCSF1抑制不促进血管快速再生

. Our studies in the OIR model have shown high levels of MCSF1 expression in the areas of pathological RNV

我们在OIR模型中的研究表明，在病理性RNV区域中MCSF1的表达水平很高

. Because macrophages can secrete MCSF1 as well as respond to it, our results suggest a proangiogenic role of MCSF1 released by activated macrophages as well as an additive effect of macrophage proliferation on pathological RNV.

由于巨噬细胞可以分泌MCSF1并对其产生反应，因此我们的结果表明活化的巨噬细胞释放的MCSF1具有促血管生成作用，以及巨噬细胞增殖对病理性RNV的累加作用。

TREM1 (triggering receptor expressed on myeloid cells 1), inflammation, and pathological RNV

TREM1（在髓样细胞1上表达的触发受体），炎症和病理性RNV

TREM1, a member of the immunoglobulin superfamily, has emerged as an important enhancer of inflammation. It activates neutrophils and monocytes/macrophages through the adapter protein DAP12

TREM1是免疫球蛋白超家族的成员，已成为炎症的重要增强剂。它通过衔接蛋白DAP12激活中性粒细胞和单核细胞/巨噬细胞

. TREM1 can be induced by several stimuli including hypoxia

TREM1可以由包括缺氧在内的多种刺激诱导

and may act as a stimulating factor for neuroinflammation. When activated in models of ischemic stroke or traumatic brain injury, TREM1 directly activates spleen tyrosine kinase (Syk) and its downstream signaling cascades in microglia

。当在缺血性中风或创伤性脑损伤模型中激活时，TREM1直接激活小胶质细胞中的脾酪氨酸激酶（Syk）及其下游信号级联

. This induces a proinflammatory microglial phenotype that can lead to neurotoxicity. Our studies in the mouse model of OIR have shown that hypoxia robustly increases expression of TREM1 together with MCSF1

。这会诱导可导致神经毒性的促炎性小胶质细胞表型。我们在OIR小鼠模型中的研究表明，缺氧会强烈增加TREM1和MCSF1的表达

. We also have found that TREM1 is localized to immune cells positive for isolectin B4, Iba1, CD45, and to MCSF1 positive immune cells in areas of pathological RNV. Moreover, specific inhibition of TREM1 blocked the pathological RNV and improved physiological vascular repair. This was the first study to show that TREM1 plays a major role in the progression of RNV in mice with OIR and suggested that activated microglia/macrophages are the main source of TREM1 expression.

我们还发现TREM1定位于病理性RNV区域中异凝集素B4，Iba1，CD45阳性的免疫细胞和MCSF1阳性的免疫细胞。此外，TREM1的特异性抑制阻断了病理性RNV并改善了生理性血管修复。这是第一项显示TREM1在OIR小鼠RNV进展中起主要作用的研究，并表明活化的小胶质细胞/巨噬细胞是TREM1表达的主要来源。

Dyslipidemia and TREM1 activation

Lipids are a major building block in all living cells. They are involved in a wide variety of structural and functional cellular processes. More than 50% of the brain’s dry weight is composed of lipids, which are found as phospholipids, sphingolipids, glycerol lipids, fatty acids, and sterols, with phospholipids accounting for ~ 50% of total lipid content.

脂质是所有活细胞的主要组成部分。它们参与多种结构和功能细胞过程。大脑干重的50%以上由脂质组成，这些脂质被发现为磷脂，鞘脂，甘油脂质，脂肪酸和甾醇，磷脂约占总脂质含量的50%。

. Functionally, lipids are key components of cell membranes including neuronal synapses and myelin sheaths. Within cell membranes they can serve to transduce signals to regulate a range of biological processes and in some circumstances act as bioenergetic fuels

在功能上，脂质是细胞膜的关键成分，包括神经元突触和髓鞘。在细胞膜内，它们可以传递信号以调节一系列生物过程，在某些情况下还可以作为生物能量燃料

. In these processes cholesterol esterification is a physiological mechanism used to store and transfer cholesterol in order to maintain cellular homeostasis and avoid cellular toxicity due to excess levels of unesterified cholesterol (also called free cholesterol)

在这些过程中，胆固醇酯化是一种生理机制，用于储存和转移胆固醇，以维持细胞稳态，并避免由于未酯化胆固醇（也称为游离胆固醇）水平过高而引起的细胞毒性

Studies in models of atherosclerosis have demonstrated a synergistic interaction between dyslipidemia and activation of TREM1 in myeloid cells that leads to increases in production of proinflammatory cytokines

动脉粥样硬化模型的研究表明，血脂异常与髓样细胞中TREM1的激活之间存在协同相互作用，从而导致促炎细胞因子的产生增加

. Furthermore, hypercholesterolemia was found to induce TREM1 expression in myeloid cells and to subsequently increase myeloid cell differentiation, thereby increasing monocyte development and promoting proatherogenic cytokine production and foam cell formation. Pharmacological blockade of TREM1 in the .

此外，发现高胆固醇血症可诱导髓样细胞中TREM1的表达，并随后增加髓样细胞的分化，从而增加单核细胞的发育并促进促动脉粥样硬化细胞因子的产生和泡沫细胞的形成。TREM1的药理学阻断。

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and high fat diet/streptozotocin-induced diabetic mouse models of type 2 diabetes has been shown to inhibit accumulation of lipid droplets, reduce inflammatory damage to hippocampal neurons, and improve cognitive functions

高脂饮食/链脲佐菌素诱导的2型糖尿病小鼠模型已被证明可以抑制脂滴的积累，减少海马神经元的炎症损伤，改善认知功能

ACAT1/SOAT1 (Acyl-coenzyme A: Cholesterol Acyltransferase 1/ Sterol O-Acyltransferase 1) and RNV

ACAT1/SOAT1（酰基辅酶A：胆固醇酰基转移酶1/固醇O-酰基转移酶1）和RNV

ACAT/SOAT are microsomal membrane-bound enzymes that are localized to the endoplasmic reticulum. They use cholesterol and long chain fatty acid as substrates to produce cholesterol esters (CE)

ACAT/SOAT是定位于内质网的微粒体膜结合酶。他们使用胆固醇和长链脂肪酸作为底物来生产胆固醇酯（CE）

. ACAT/SOAT enzymes are expressed in many tissues including brain, retina, liver, and other tissues, where they are involved in formation and accumulation of CE

。ACAT/SOAT酶在许多组织中表达，包括脑，视网膜，肝脏和其他组织，它们参与CE的形成和积累

. In mammals, ACAT/SOAT exists as two isoforms: ACAT1/SOAT1 and ACAT2/SOAT2. Most tissues express ACAT1/SOAT1 as the major isoform and ACAT2/SOAT2 as a minor isoform

在哺乳动物中，ACAT/SOAT以两种同工型存在：ACAT1/SOAT1和ACAT2/SOAT2。大多数组织表达ACAT1/SOAT1为主要亚型，ACAT2/SOAT2为次要亚型

. Both isoforms are allosterically activated by their substrate (cholesterol or oxysterols). Cholesterol activates ACAT1/SOAT1, induces its expression allosterically, and is more effective than other sterols in this effect.

两种同工型均被其底物（胆固醇或氧固醇）变构激活。胆固醇激活ACAT1/SOAT1，变构诱导其表达，并且在这种作用下比其他固醇更有效。

High levels of ACAT1/SOAT1 activity have been shown in a variety of disease conditions, including cancer, Alzheimer’s disease, and cardiovascular disease

高水平的ACAT1/SOAT1活性已在多种疾病中显示出来，包括癌症，阿尔茨海默氏病和心血管疾病

. Studies using macrophages have shown that internalization of low density lipoprotein (LDL) cholesterol by the LDL receptor and the resulting increases in intracellular cholesterol levels increase ACAT1/SOAT1 activity which leads to increases in CE formation

使用巨噬细胞的研究表明，低密度脂蛋白受体对低密度脂蛋白（LDL）胆固醇的内在化以及由此产生的细胞内胆固醇水平的增加会增加ACAT1/SOAT1活性，从而导致CE形成的增加

. Our studies in the OIR mouse model have shown that increased expression of inflammatory mediators and pathological RNV are associated with increased expression of LDLR, increased accumulation of neutral lipids, and elevated levels of CE in areas of RNV along with high expression of ACAT1/SOAT1

我们在OIR小鼠模型中的研究表明，炎症介质和病理性RNV的表达增加与LDLR表达增加，中性脂质积累增加，RNV区域CE水平升高以及ACAT1/SOAT1高表达有关

. ACAT2/SOAT2 expression was unchanged during OIR. The ACAT1/SOAT1 protein was colocalized with TREM1, MCSF1, and markers of macrophage and microglial cells in areas of pathological RNV. Consistent with these findings, recent lipidomic analysis showed marked elevation of cholesterol esterification, lipid droplet formation, reversed cholesterol transport, and increased concentration of n-9 fatty acids along with increased expression of ACAT1/SOAT1 in the OIR retinas at P17 as compared with the room air controls.

在OIR期间，ACAT2/SOAT2的表达没有变化。ACAT1/SOAT1蛋白与TREM1，MCSF1以及病理性RNV区域中巨噬细胞和小胶质细胞的标志物共定位。与这些发现一致，最近的脂质组学分析显示，与室内空气对照相比，P17处OIR视网膜中胆固醇酯化，脂滴形成，胆固醇转运逆转，n-9脂肪酸浓度增加以及ACAT1/SOAT1表达增加。

Our studies further showed that deletion of the LDL receptor completely blocks pathological RNV which indicates a critical role of LDL cholesterol uptake in the pathology

我们的研究进一步表明，低密度脂蛋白受体的缺失完全阻断了病理性RNV，这表明低密度脂蛋白胆固醇摄取在病理学中起着关键作用

. Moreover, treatment with the specific inhibitor of ACAT1/SOAT1 K604 during the relative hypoxia phase of OIR significantly inhibited the increases in inflammatory mediators and limited the pathological RNV while reducing the avascular area, indicating involvement of CE formation in the pathology. Also, OIR-induced increases in retinal ACAT1/SOAT1 expression/activity together with high levels of CE formation and accumulation of neutral lipids were associated with increases in the expression of VEGF.

此外，在OIR的相对缺氧阶段，用ACAT1/SOAT1 K604特异性抑制剂治疗可显着抑制炎症介质的增加，并限制病理性RNV，同时减少无血管面积，表明CE形成参与病理。此外，OIR诱导的视网膜ACAT1/SOAT1表达/活性的增加以及高水平的CE形成和中性脂质的积累与VEGF表达的增加有关。

In contrast with the effects of K604 treatment in reducing signs of inflammation and limiting the pathological RNV, VEGF expression was not affected.

与K604治疗在减少炎症迹象和限制病理性RNV方面的作用相反，VEGF表达不受影响。

. Our studies using microglial cells exposed to oxygen-glucose deprivation (OGD) under in vitro conditions further showed marked increases in expression of ACAT1/SOAT1, TREM1, and MCSF along with significant increases in expression of VEGF

我们在体外条件下使用暴露于氧糖剥夺（OGD）的小胶质细胞进行的研究进一步表明，ACAT1/SOAT1，TREM1和MCSF的表达显着增加，而VEGF的表达显着增加

. Treatment with the K604 ACAT1/SOAT1 inhibitor blocked each of these effects except for the increase in VEGF expression.

用K604 ACAT1/SOAT1抑制剂治疗可阻断除VEGF表达增加外的每种作用。

These data suggest that the increase in VEGF expression in the models of OIR or OGD is independent of ACAT1/SOAT1 activity. Although intravitreal injections of anti-VEGF are often used to treat RNV, potential side effects can limit its use

这些数据表明，OIR或OGD模型中VEGF表达的增加与ACAT1/SOAT1活性无关。尽管玻璃体内注射抗VEGF通常用于治疗RNV，但潜在的副作用可能会限制其使用

. VEGF is a critical survival factor required for physiological vascular growth and repair

VEGF是生理血管生长和修复所需的关键生存因子

. In our OIR study we also observed increased numbers of tip cells sprouting into the avascular area of retinas of OIR mice treated with K604 and a reduction in the avascular area as compared with the vehicle treated ischemic retinas. This suggests that inhibition of ACAT1/SOAT1 can limit pathological RNV while preserving normal VEGF expression and thereby promoting physiological vascular repair.

在我们的OIR研究中，我们还观察到，与媒介物处理的缺血性视网膜相比，用K604处理的OIR小鼠的视网膜无血管区域发芽的尖端细胞数量增加，无血管区域减少。这表明抑制ACAT1/SOAT1可以限制病理性RNV，同时保持正常的VEGF表达，从而促进生理性血管修复。

This strategy may offer an effective therapy for pathological neovascularization. Figure .

该策略可能为病理性新血管形成提供有效的治疗方法。图。

illustrates a suggested signaling pathway involved in ACAT1/SOAT1-induced RNV.

说明了涉及ACAT1/SOAT1诱导的RNV的建议信号传导途径。

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

图1：将血脂异常与巨噬细胞/小胶质细胞诱导的RNV联系起来的步骤的简化示意图。

Enhanced LDL-cholesterol uptake

增强低密度脂蛋白胆固醇摄取

: Under hypoxic/ischemic conditions, macrophages/microglia show increased expression of LDL-receptor (LDLR) and increased internalization of LDL-cholesterol (LDL-C). 2)

：在缺氧/缺血条件下，巨噬细胞/小胶质细胞显示LDL受体（LDLR）表达增加，LDL胆固醇（LDL-C）内化增加。二）

Activation of ACAT1/SOAT1

激活ACAT1/SOAT1

: Hypoxic/ischemic conditions promote increased cholesterol uptake along with increased ACAT1/SOAT1 activity which increases CE formation. 3)

：缺氧/缺血条件促进胆固醇摄取增加，同时ACAT1/SOAT1活性增加，从而增加CE的形成。三）

ROS mediated oxidation of CE

: Ischemia induces ROS formation, which leads to CE oxidation (Ox-CE) via activation of radical and nonradical modification pathways

：缺血诱导ROS形成，通过激活自由基和非自由基修饰途径导致CE氧化（Ox-CE）

. 4)

Induction of Inflammation signaling

炎症信号的诱导

: Ox-CE can activate

：Ox CE可以激活

TREM1

through TLR4

通过TLR4

. TREM1 induces inflammation by activating the DAP12/Syk (spleen tyrosine kinase) signaling cascade. TREM1 inhibition decreases levels of inflammatory cytokines

TREM1通过激活DAP12/Syk（脾酪氨酸激酶）信号级联反应诱导炎症。TREM1抑制降低炎性细胞因子水平

. 5)

Release of proinflammatory cytokines

促炎细胞因子的释放

: 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

：TREM1诱导核因子-κB（NFκβ）信号通路，导致产生促炎细胞因子，例如IL6，IL1β，TNFα，MCSF

Retinal neovascularization

视网膜新生血管

: 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.

：活化的巨噬细胞/小胶质细胞在调节血管生成中起关键作用，并与RNV的发病机制密切相关。在BioRender中创建。。

Full size image

全尺寸图像

Dyslipidemia, macrophage activation, and inflammation

血脂异常，巨噬细胞活化和炎症

Our studies have implicated ACAT1/SOAT1 activity and CE formation in the OIR-induced increases in expression of LDLR and TREM1 along with MCSF1 as well as inflammatory cytokines [59]. We and others have shown that TNFα is involved in pathological RNV, breakdown of the blood retinal barrier, and ACAT1/SOAT1 expression.

。我们和其他人已经证明，TNFα参与病理性RNV，血-视网膜屏障的破坏和ACAT1/SOAT1的表达。

. The mechanism of hyperlipidemia-induced macrophage activation and the role of TREM1 in the process are not fully understood. While several endogenous ligands for TREM1 have been identified, the mechanism of their activation is still not clear

高脂血症诱导的巨噬细胞活化的机制以及TREM1在该过程中的作用尚不完全清楚。虽然已经确定了TREM1的几种内源性配体，但其激活机制仍不清楚

One possible mechanism may involve activation of the toll like receptor 4 (TLR4)-Syk pathway. In a macrophage model of dyslipidemia, activation of TLR4 has been shown to play a key role in ROS formation. Stimulation of peritoneal macrophages with minimally modified LDL cholesterol (mmLDL) has been shown to promote significant increases in NOX2-derived ROS leading to increases in expression of inflammatory cytokines.

一种可能的机制可能涉及激活toll样受体4（TLR4）-Syk途径。在血脂异常的巨噬细胞模型中，TLR4的激活已被证明在ROS形成中起关键作用。已显示用最小修饰的LDL胆固醇（mmLDL）刺激腹膜巨噬细胞可促进NOX2衍生的ROS的显着增加，从而导致炎性细胞因子的表达增加。

. This effect was completely blocked in TLR4 knockout mice. In contrast, macrophages from MyD88 (myeloid differentiation primary response protein) knockout mice showed a normal ROS response. This suggests that mmLDL cholesterol-induced NOX2 derived ROS production in macrophages depends on the presence of TLR4 but not MyD88.

这种作用在TLR4基因敲除小鼠中被完全阻断。相反，来自MyD88（骨髓分化初级反应蛋白）敲除小鼠的巨噬细胞显示出正常的ROS反应。。

Also, LDL cholesterol-induced activation of TLR4 in macrophages has been shown to involve TLR4-mediated Syk activation and downstream signaling. J774 macrophages stimulated with LDL cholesterol showed increased coimmunoprecipitation of Syk with TLR4.

此外，已显示LDL胆固醇诱导的巨噬细胞中TLR4的激活涉及TLR4介导的Syk激活和下游信号传导。用LDL胆固醇刺激的J774巨噬细胞显示Syk与TLR4的免疫共沉淀增加。

. In a recent study using microglial N9 cells, it was found that blocking ACAT1 with K604 significantly reduced the proinflammatory responses induced by LPS. K604 decreased the total TLR4 protein content by promoting TLR4 endocytosis, which enhanced the trafficking of TLR4 to the lysosomes for degradation.

在最近一项使用小胶质细胞N9细胞的研究中，发现用K604阻断ACAT1可显着降低LPS诱导的促炎反应。K604通过促进TLR4内吞作用降低了总TLR4蛋白含量，从而增强了TLR4向溶酶体的运输以进行降解。

This suppression of TLR4 resulted in the inhibition of its proinflammatory signaling cascade in response to LPS.

TLR4的这种抑制导致其响应LPS的促炎信号级联反应的抑制。

. The mechanism of this effect is as yet unknown, but may involve ACAT1/SOAT1 inhibitor-induced alterations in TLR4 membrane microdomains that cause it to undergo an increase in caveolae-mediated endocytosis.

这种作用的机制尚不清楚，但可能涉及ACAT1/SOAT1抑制剂诱导的TLR4膜微区的改变，导致其经历细胞膜穴样内陷介导的内吞作用的增加。

Another likely mechanism is that oxidized CE could be involved. Studies have shown that oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) works as a specific oxidized CE to activate macrophages in a TREM2/MD2 (myeloid differentiation factor 2)-dependent manner.

。研究表明，具有双环内过氧化物和氢过氧化物基团的氧化胆固醇花生四烯酸（BEP-CE）作为特定的氧化CE以TREM2/MD2（髓样分化因子2）依赖性方式激活巨噬细胞。

. MD2 is a TREM2 binding protein that dimerizes with TLR4 and is required for TLR4 activation. BEP-CE induces TLR4/MD2 binding and TLR4 dimerization which promotes phosphorylation of SyK, ERK1/2, JNK and c-Jun, cell spreading, and uptake of dextran and native LDL cholesterol by macrophages

MD2是一种TREM2结合蛋白，与TLR4二聚化，是TLR4激活所必需的。BEP-CE诱导TLR4/MD2结合和TLR4二聚化，促进SyK，ERK1/2，JNK和c-Jun的磷酸化，细胞扩散以及巨噬细胞摄取葡聚糖和天然LDL胆固醇

. Taken together, these results suggest involvement of different sources of free radicals in the process of beta oxidation of LDL cholesterol which converts CEs into active forms capable of activating other enzymes or inducing the expression on other proteins. More studies are needed to fully elucidate the TREM1/TLR4/ SyK signaling pathway in ischemic retinopathy..

综上所述，这些结果表明不同来源的自由基参与了LDL胆固醇的β-氧化过程，该过程将CE转化为能够激活其他酶或诱导其他蛋白质表达的活性形式。需要更多的研究来充分阐明缺血性视网膜病变中的TREM1/TLR4/SyK信号通路。。

Conclusion

结论

We have demonstrated a novel strategy to limit pathological RNV and promote physiological repair in the mouse OIR model by inhibiting ACAT1/SOAT1 activity and thereby preventing CE formation and blocking activation of TREM1. The mechanism behind hypoxia-induced inflammation and macrophage/microglia activation is not yet clear.

我们已经证明了一种新的策略，通过抑制ACAT1/SOAT1活性来限制病理性RNV并促进小鼠OIR模型中的生理修复，从而防止CE形成并阻断TREM1的激活。缺氧诱导的炎症和巨噬细胞/小胶质细胞活化背后的机制尚不清楚。

Our studies in the OIR model have shown that LDLR is induced by hypoxia and that LDLR deletion completely blocks intravitreal RNV.

我们在OIR模型中的研究表明，LDLR是由缺氧诱导的，LDLR缺失完全阻断了玻璃体内RNV。

which strongly supports the role of LDL cholesterol uptake in the pathology. In the OIR model, inhibition of ACAT1/SOAT1 significantly reduces inflammation and inhibits pathological RNV while improving vascular repair without altering VEGF expression. Anti-VEGF therapy during ischemic retinopathy is associated with some risks of neurovascular dysfunction since VEGF is a survival factor required for retinal neuronal function and vascular repair, especially during OIR.

这有力地支持了LDL胆固醇摄取在病理学中的作用。在OIR模型中，抑制ACAT1/SOAT1显着减少炎症并抑制病理性RNV，同时改善血管修复而不改变VEGF表达。缺血性视网膜病变期间的抗VEGF治疗与神经血管功能障碍的一些风险相关，因为VEGF是视网膜神经元功能和血管修复所需的生存因子，尤其是在OIR期间。

Collectively, dysregulation of retinal lipid metabolism in ischemic retinopathy can impact a variety of factors involved in inflammation and neurovascular damage and therefore visual functions. In summary targeting ACAT1/SOAT1 activity offers a novel strategy for treatment of ischemic retinopathies and other diseases that involve pathological RNV..

总的来说，缺血性视网膜病变中视网膜脂质代谢的失调会影响炎症和神经血管损伤以及视觉功能的多种因素。总之，靶向ACAT1/SOAT1活性为治疗缺血性视网膜病变和其他涉及病理性RNV的疾病提供了一种新策略。。

Limitations and future directions

局限性和未来方向

Under normal conditions ACAT1/SOAT1 is important for a variety of homeostatic functions, particularly in relation to immune function. However research in models of Alzheimer’s and cardiovascular disease has shown that excessive CE formation leads to the activation of myeloid cells and subsequently to cellular damage and that this can be blocked by inhibiting ACAT1/SOAT1 activity.

在正常情况下，ACAT1/SOAT1对于多种稳态功能很重要，特别是与免疫功能有关。然而，对阿尔茨海默氏病和心血管疾病模型的研究表明，过量的CE形成会导致髓样细胞活化，进而导致细胞损伤，这可以通过抑制ACAT1/SOAT1活性来阻断。

. While the mechanism of this protective action is not fully established, results of studies using a model of LPS-induced neuroinflammation suggest that this protective effect involves alterations in the caveolae/lipid raft region of the plasma membrane

虽然这种保护作用的机制尚未完全确定，但使用LPS诱导的神经炎症模型的研究结果表明，这种保护作用涉及质膜小窝/脂筏区域的改变

The above mentioned work in Alzheimer’s and cardiovascular disease models has shown that blockade of ACAT1/SOAT1 can limit disease pathology without impairing normal physiological functions. However considering that neonatal mice are undergoing normal development, we monitored body weight, motility, behavior, and plasma levels of cytokines and lipid profiles after treatment with the ACAT1/SOAT1 inhibitor or vehicle control.

上述在阿尔茨海默病和心血管疾病模型中的工作表明，阻断ACAT1/SOAT1可以限制疾病病理而不损害正常的生理功能。然而，考虑到新生小鼠正在经历正常发育，我们在用ACAT1/SOAT1抑制剂或媒介物对照治疗后监测了体重，运动性，行为以及血浆细胞因子和血脂水平。

Those analyses showed no adverse effects with the inhibitor treatment. Our data further showed that inhibitor treatment over a period of 10 days inhibits pathological RNV and promotes physiological vascular repair while limiting vision loss tested after the mice mature. In comparison with anti-VEGF, the ACAT1/SOAT1 inhibitor treatment should be safer since blocking VEGF affects all cells that require it for their normal function including neurons as well as vascular endothelial cells..

这些分析显示抑制剂治疗没有不良反应。我们的数据进一步表明，抑制剂治疗10天可抑制病理性RNV并促进生理性血管修复，同时限制小鼠成熟后测试的视力丧失。与抗VEGF相比，ACAT1/SOAT1抑制剂治疗应该更安全，因为阻断VEGF会影响所有需要其正常功能的细胞，包括神经元和血管内皮细胞。。

In our study we did not identify subtypes of CEs. Their identification will be key to defining more clearly the role of CE in this pathology. To access this, correlating a lipidomic analysis with studies of the expression of ACAT1/SOAT1, TREM1, MCSF1, VEGF and inflammatory cytokines should be a priority.

在我们的研究中，我们没有确定CE的亚型。他们的鉴定将是更清楚地定义CE在这种病理学中的作用的关键。为了获得这一点，应优先将脂质组学分析与ACAT1/SOAT1，TREM1，MCSF1，VEGF和炎性细胞因子表达的研究相关联。

Our further studies will explore the known markers of retinal neuronal damage, including vascular permeability, leukocyte adhesion, acellular capillary formation, retinal inflammation, and oxidative stress in relation to the tissue damage induced by ACAT1/SOAT1 in models of diabetic retinopathy (i.e., Akita mice, STZ-induced diabetic mice, .

我们的进一步研究将探索视网膜神经元损伤的已知标志物，包括血管通透性，白细胞粘附，无细胞毛细血管形成，视网膜炎症和与糖尿病视网膜病变模型（即秋田小鼠，STZ诱导的糖尿病小鼠）中ACAT1/SOAT1诱导的组织损伤相关的氧化应激。

db/db

分贝/分贝

mice). Studies using strategies for deletion of ACAT1/SOAT1 in macrophage and retinal microglial cells will give us a better understanding of the underlying mechanisms.

小鼠）。使用巨噬细胞和视网膜小胶质细胞中ACAT1/SOAT1缺失策略的研究将使我们更好地了解其潜在机制。

Data availability

数据可用性

No datasets were generated or analysed during the current study.

在当前的研究中，没有生成或分析数据集。

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Acknowledgements

致谢

We acknowledge Ta-Yuan Chang, PhD, and Catherine Chung-Yao Chang, PhD, Geisel School of Medicine, Hanover, NH for providing feedback. We also acknowledge Dhruvi Pandya, Medical Student at MCG for reading and suggesting corrections. The figure was generated using BioRender, under CC-BY licensing (Creative Commons).

我们感谢新罕布什尔州汉诺威市Geisel医学院的Ta Yuan Chang博士和Catherine Chung Yao Chang博士提供的反馈。我们也感谢MCG医学生Dhruvi Pandya的阅读和建议。该数字是在CC-BY许可（知识共享）下使用BioRender生成的。

This study was supported by grants from the National Institute of Health R21EY032265 and 1R01EY035683 to MAR and RBC, and P30EY031631 to the Culver Vision Discovery Institute at Augusta University..

。。

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These authors contributed equally: Syed A. H. Zaidi, Modesto A. Rojas.

这些作者做出了同样的贡献：Syed A.H.Zaidi，Modesto A.Rojas。

Authors and Affiliations

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Vascular Biology Center, Augusta University, Augusta, GA, 30912, USA

血管生物学中心，奥古斯塔大学，奥古斯塔，佐治亚州，30912，美国

Syed A. H. Zaidi, Ruth B. Caldwell & Modesto A. Rojas

赛义德A。H。扎伊迪，露丝B。考德威尔和莫德斯托A。罗哈斯

Vision Discovery Institute, Augusta University, Augusta, GA, 30912, USA

奥古斯塔大学视觉发现研究所，奥古斯塔，佐治亚州，30912，美国

Syed A. H. Zaidi, Ruth B. Caldwell & Modesto A. Rojas

赛义德A。H。扎伊迪，露丝B。考德威尔和莫德斯托A。罗哈斯

Department of Medicine, Augusta University, Augusta, GA, 30912, USA

奥古斯塔大学医学系，佐治亚州奥古斯塔，30912，美国

Syed A. H. Zaidi

Syed A.H.更多

Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, 30912, USA

奥古斯塔大学细胞生物学与解剖学系，美国佐治亚州奥古斯塔30912

Ruth B. Caldwell

露丝·B·考德威尔

Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, 30912, USA

奥古斯塔大学药理学和毒理学系，佐治亚州奥古斯塔，30912，美国

Modesto A. Rojas

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MAR wrote the first draft of the perspective. SAHZ and RBC provided critical feedback and revised the manuscript. SAHZ prepared the figure with input from MAR and RBC. SAHZ and MAR share equal first authorship for this article. Both RBC and MAR share correspondence for this article. All authors revised and approved the final manuscript..

马尔写了《透视图》的初稿。SAHZ和RBC提供了重要的反馈并修改了手稿。SAHZ根据MAR和RBC的输入准备了这个数字。SAHZ和MAR在本文中拥有同等的第一作者身份。RBC和MAR都有本文的通信。所有作者都修改并批准了最终稿件。。

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Zaidi, S.A.H., Caldwell, R.B. & Rojas, M.A. Myeloid ACAT1/SOAT1: a novel regulator of dyslipidemia and retinal neovascularization.

Zaidi，S.A.H.，Caldwell，R.B。＆Rojas，M.A。髓样ACAT1/SOAT1：血脂异常和视网膜新生血管形成的新型调节剂。

npj Metab Health Dis