Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E–deficient (Apoe^−/−) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe^−/− with human apoprotein A1–transgenic (APOA1^tg/tg) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe^−/− and APOA1^tg/tg/Apoe^−/− mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for 4 more weeks. Plaques of APOA1^tg/tg/Apoe^−/− mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison with Apoe^−/− baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis.

中文翻译：

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短期酰基辅酶A：胆固醇酰基转移酶抑制，结合载脂蛋白A1过表达，促进小鼠动脉粥样硬化炎症消退

酰基辅酶A：胆固醇酰基转移酶（ACAT）介导细胞胆固醇酯化。在动脉粥样硬化斑块巨噬细胞中，ACAT 促进胆固醇酯积累，导致泡沫细胞形成和动脉粥样硬化进展。然而，它在小鼠中的完全失活显示出毒性作用，因为巨噬细胞中游离胆固醇 (FC) 过量，这会导致内质网应激、胆固醇晶体形成和炎性体激活。我们之前的研究表明，通过膳食补充 Fujirebio F1394 实现的长期部分 ACAT 抑制可延缓载脂蛋白 E 缺乏的动脉粥样硬化进展 ( Apoe ^-/-) 小鼠通过减少斑块泡沫细胞的形成而没有炎症或毒性作用。在这里，我们确定了 ACAT 的短期部分抑制与增强的系统性 FC 受体能力相结合是否具有协同效应。因此，我们将 Apoe ^-/-与具有升高的胆固醇流出高密度脂蛋白颗粒的人类载脂蛋白 A1 转基因 ( APOA1 ^{tg/tg ) 小鼠杂交，并对}Apoe ^-/-和APOA1 ^tg/tg / Apoe ^-/-小鼠致动脉粥样硬化饮食以发展晚期斑块。然后将小鼠安乐死（基线）或喂食含有或不含 F1394 的纯化标准饮食 4 周以上。APOA1斑块与Apoe ^-/-基线小鼠相比，喂食 F1394 的^tg/tg / Apoe ^-/-小鼠的巨噬细胞减少了 60%，并伴有多种其他益处，例如炎症减少和细胞外成分的有利变化。此外，没有胆固醇晶体的积累或毒性迹象。总体而言，这些结果表明，短期部分 ACAT 抑制，加上增加的胆固醇流出能力，有利于重塑动脉粥样硬化病变，支持这些联合疗法在治疗晚期动脉粥样硬化中的潜力。