Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation.
Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation.
复制标题
载脂蛋白 A-I Helsinki 促进细胞内酰基辅酶 A 胆固醇酰基转移酶 (ACAT) 蛋白积累。
DOI：
10.1007/s11010-013-1585-y
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发表时间：
2013
影响因子：
4.3
通讯作者：
Gonzalez,MarinaC
中科院分区：
文献类型：
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作者：
Toledo,JuanD;Garda,HoracioA;Cabaleiro,LauraV;Cuellar,Angela;Pellon-Maison,Magali;Gonzalez-Baro,MariaR;Gonzalez,MarinaC
胆固醇反向转运是一个具有高度抗动脉粥样硬化相关性的过程，其中载脂蛋白 AI (apoA-I) 发挥着重要作用。 apoA-I 与外周细胞的相互作用通过仍知之甚少的机制产生细胞内胆固醇库向质膜的动员。在巨噬细胞中，这些机制似乎与酰基辅酶A胆固醇酰基转移酶（ACAT）活性的调节有关，该酶负责储存在脂滴中的细胞内胆固醇酯生物合成。 ACAT的激活和脂滴的积累在巨噬细胞转化为泡沫细胞、导致动脉粥样硬化或动脉粥样硬化斑块的形成过程中发挥着关键作用。 ApoA-I Helsinki（或 ΔK107）是一种天然的 apoA-I 变体，其中央蛋白质区域存在赖氨酸缺失，其携带者会增加动脉粥样硬化的风险。我们在此表明，用 ΔK107 处理培养的 RAW 巨噬细胞或 CHOK1 细胞，而不是用野生型 apoA-I 或 C 端区域包含类似缺失的变体 (ΔK226) 处理，会导致细胞内 ACAT1 蛋白水平显着增加（超过 10 倍），如通过蛋白质印迹分析检测到的。然而，我们只能检测到 ΔK107 产生的胆固醇酯略有增加，主要是当胆负载由低密度脂蛋白 (LDL) 提供时。尽管这些 apoA-I 变体引起类似的胆碱-磷脂外流，但在 ΔK107 或 ΔK226 中均未观察到野生型 apoA-I 产生的磷脂酰胆碱/鞘磷脂分布的变化。
Reverse cholesterol transport is a process of high antiatherogenic relevance in which apolipoprotein AI (apoA-I) plays an important role. The interaction of apoA-I with peripheral cells produces through mechanisms that are still poorly understood the mobilization of intracellular cholesterol depots toward plasma membrane. In macrophages, these mechanisms seem to be related to the modulation of the activity of acyl-CoA cholesterol acyltransferase (ACAT), the enzyme responsible for the intracellular cholesterol ester biosynthesis that is stored in lipid droplets. The activation of ACAT and the accumulation of lipid droplets play a key role in the transformation of macrophages into foam cells, leading to the formation of atheroma or atherosclerotic plaque. ApoA-I Helsinki (or ∆K107) is a natural apoA-I variant with a lysine deletion in the central protein region, carriers of which have increased atherosclerosis risk. We herein show that treatment of cultured RAW macrophages or CHOK1 cells with ∆K107, but not with wild-type apoA-I or a variant containing a similar deletion at the C-terminal region (∆K226), lead to a marked increase (more than 10 times) in the intracellular ACAT1 protein level as detected by western blot analysis. However, we could only detect a slight increase in cholesteryl ester produced by ∆K107 mainly when Chol loading was supplied by low-density lipoprotein (LDL). Although a similar choline-phospholipid efflux is evoked by these apoA-I variants, the change in phosphatidylcholine/sphyngomyelin distribution produced by wild-type apoA-I is not observed with either ∆K107 or ∆K226.