Deletion of lysophosphatidylcholine acyltransferase 3 in myeloid cells worsens hepatic steatosis after a high-fat diet.
Deletion of lysophosphatidylcholine acyltransferase 3 in myeloid cells worsens hepatic steatosis after a high-fat diet.
复制标题
髓样细胞中溶物磷脂酰胆碱转移酶3的缺失会在高脂饮食后恶化肝脂肪变性。
DOI：
10.1194/jlr.ra120000737
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发表时间：
2021
影响因子：
6.5
通讯作者：
Grober J
中科院分区：
文献类型：
--
作者：
Bourgeois T;Jalil A;Thomas C;Magnani C;Le Guern N;Gautier T;Pais de Barros JP;Bergas V;Choubley H;Mazzeo L;Menegaut L;Josiane Lebrun L;Van Dongen K;Xolin M;Jourdan T;Buch C;Labbé J;Saas P;Lagrost L;Masson D;Grober J
最近的研究强调了溶血磷脂酰胆碱酰基转移酶3（LPCAT 3）在控制肝脏和肠道细胞膜PUFA组成中的重要作用。在这些器官中，LPCAT 3关键支持细胞膜相关过程，如脂质吸收或脂蛋白分泌。然而，LPCAT 3在巨噬细胞中的作用仍然存在争议。在这里，我们研究了LPCAT 3在体外和体内患有动脉粥样硬化和肥胖的小鼠中的巨噬细胞中的作用。为了实现这一点，我们使用LysMCre策略来开发骨髓细胞中具有条件性Lpcat 3缺陷的小鼠模型（Lpcat 3 KOMac）。我们观察到，部分Lpcat 3缺陷（约75%的减少）在巨噬细胞改变PUFA组成的所有磷脂（PL）亚类，包括磷脂酰肌醇和磷脂酰丝氨酸。减少C20 PUFA（主要是花生四烯酸[AA]）掺入PL与这些FA向其他细胞脂质（如胆固醇酯）的再分配有关。Lpcat 3缺陷对巨噬细胞炎症反应或内质网（ER）应激没有明显影响;然而，Lpcat 3 KOMac巨噬细胞在体外表现出胆固醇流出减少。在体内，髓样Lpcat 3缺陷并不影响LDL受体缺陷小鼠（Ldlr−/−）动脉粥样硬化的发展。高脂饮食的Lpcat 3 KOMac小鼠显示与几种肝脏代谢途径和肝脏类花生酸组成改变相关的肝脏脂肪变性轻度增加。我们的结论是，AA代谢的改变沿着髓样Lpcat 3缺乏可能继发影响AA在整个肝脏中的稳态，导致代谢紊乱和甘油三酯积累。
Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell-membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3's role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approximately 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr−/−) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.