Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1
Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1
复制标题
DOI：
10.1172/jci9021
复制
发表时间：
2000-03-01
影响因子：
15.9
通讯作者：
Farese, RV
中科院分区：
文献类型：
--
作者：
Accad, M;Smith, SJ;Farese, RV
酰基辅酶A：胆固醇酰基转移酶（ACAT）的抑制剂作为动脉粥样硬化的潜在治疗方法已经引起了相当大的兴趣。目前可用的抑制剂可能对两种已知的ACATs起非选择性作用。这些酶之一，ACAT 1，在动脉粥样硬化病变的巨噬细胞中高度表达，在那里它有助于泡沫细胞形成。在这项研究中，我们研究了选择性ACAT 1缺陷在两种小鼠动脉粥样硬化模型中的作用。在由apoE或LDL受体（LDLR）缺乏引起的严重高胆固醇血症的情况下，总ACAT 1缺乏导致胆固醇稳态的显著改变和皮肤和大脑中未酯化胆固醇的广泛沉积。骨髓移植实验表明，巨噬细胞中的ACAT 1缺陷足以导致高脂血症LDL受体缺陷小鼠的皮肤黄瘤。ACAT1缺陷并不能阻止apoE缺陷或LDLR缺陷小鼠动脉粥样硬化病变的发展，尽管会导致相对较低的血清胆固醇水平。然而，ACAT1缺陷小鼠的病变在组成上是非典型的，在晚期病变中中性脂质量减少，巨噬细胞缺乏。虽然后一项发现可能与病变稳定性增加有关，但胆固醇稳态的显著改变表明，在严重高脂血症的情况下选择性抑制ACAT 1可能会产生有害后果。
Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.