<br>由甘油-3-磷酸酰基转移酶-3和-4指导的三酰甘油合成是巨噬细胞向泡沫细胞转变过程中脂滴形成和炎症反应调节所必需的,Atherosclerosis

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由甘油-3-磷酸酰基转移酶-3和-4指导的三酰甘油合成是巨噬细胞向泡沫细胞转变过程中脂滴形成和炎症反应调节所必需的
Atherosclerosis ( IF 4.9 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.atherosclerosis.2020.11.022
Ivana Y Quiroga ₁ , Magali Pellon-Maison ₁ , Marina C Gonzalez ₁ , Rosalind A Coleman ₂ , Maria R Gonzalez-Baro ₁

Affiliation

背景和目的巨噬细胞向泡沫细胞的转变是早期动脉粥样硬化病变的主要标志。该过程的特点是含有大量胆固醇酯（CE）、三酰甘油（TAG）和磷脂（PL）的大细胞质脂滴的积累。尽管泡沫细胞形成过程中的胆固醇和 CE 代谢已得到广泛研究，但人们对甘油脂（TAG 和 PL）在此背景下的作用知之甚少。在这里，我们研究了甘油脂合成对脂质积累的贡献，特别关注该途径的第一个限速酶：甘油-3-磷酸酰基转移酶（GPAT）。方法我们使用用氧化低密度脂蛋白 (oxLDL) 处理的 RAW 264.7 细胞和骨髓源性巨噬细胞 (BMDM)。结果我们发现巨噬细胞向泡沫细胞转变期间诱导了 TAG 合成。在此过程中，GPAT3和GPAT4的表达和活性也增加，这两种异构体是细胞TAG和PL积累所必需的。与巨噬细胞向泡沫细胞转变后的野生型小鼠细胞相比，Gpat4-/- BMDM 释放更多促炎细胞因子和趋化因子，表明 GPAT4 的活性可能与炎症反应的减少有关，可能是通过将信号前体隔离在脂滴。结论我们的结果提供了证据，表明 GPAT3 和 GPAT4 指导的 TAG 合成是巨噬细胞-泡沫细胞转变过程中脂滴形成和炎症反应调节所必需的。

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Triacylglycerol synthesis directed by glycerol-3-phosphate acyltransferases -3 and -4 is required for lipid droplet formation and the modulation of the inflammatory response during macrophage to foam cell transition

BACKGROUND AND AIMS The transition of macrophage to foam cells is a major hallmark of early stage atherosclerotic lesions. This process is characterized by the accumulation of large cytoplasmic lipid droplets containing large quantities of cholesterol esters (CE), triacylglycerol (TAG) and phospholipid (PL). Although cholesterol and CE metabolism during foam cell formation has been broadly studied, little is known about the role of the glycerolipids (TAG and PL) in this context. Here we studied the contribution of glycerolipid synthesis to lipid accumulation, focusing specifically on the first and rate-limiting enzyme of the pathway: glycerol-3-phosphate acyltransferase (GPAT). METHODS We used RAW 264.7 cells and bone marrow derived macrophages (BMDM) treated with oxidized LDL (oxLDL). RESULTS We showed that TAG synthesis is induced during the macrophage to foam cell transition. The expression and activity of GPAT3 and GPAT4 also increased during this process, and these two isoforms were required for the accumulation of cell TAG and PL. Compared to cells from wildtype mice after macrophage to foam cell transition, Gpat4-/- BMDM released more pro-inflammatory cytokines and chemokines, suggesting that the activity of GPAT4 could be associated with a decrease in the inflammatory response, probably by sequestering signaling precursors into lipid droplets. CONCLUSIONS Our results provide evidence that TAG synthesis directed by GPAT3 and GPAT4 is required for lipid droplet formation and the modulation of the inflammatory response during the macrophage-foam cell transition.

更新日期：2021-01-01

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