Abstract
Mammalian cell membrane phosphatidylcholines (PCs), the major phospholipids, exhibit diversity which is controlled by Lands' cycle or PC remodeling pathway. Lysophosphatidylcholine acyltransferase (LPCAT) is one of the major players in the pathway and plays an important role in maintaining cell membrane structure and function. LPCAT3 is highly expressed in macrophages, however, its role in mediating inflammation is still not understood, since contradictory results were reported previously. The order of LPCAT mRNA levels in mouse macrophages is as follows: LPCAT3 > LPCAT1 > LPCAT2 >> LPCAT4. In order to investigate the role of LPCAT3 in macrophages, we prepared myeloid cell-specific Lpcat3 knockout (KO) mice and found that the deficiency significantly reduced certain polyunsaturated phosphatidylcholines, such as 16:0/20:4, 18:1/18:2, 18:0/20:4, and 18:1/20:4 in macrophage plasma membrane. Lpcat3 deficiency significantly increased toll like receptor 4 protein and phosphorylated c-Src in membrane lipid rafts, and increased LPS-induced IL-6 and TNFα releasing through activation of MAP kinases and NFκB. Moreover, the ablation of LPCAT3 in macrophages significantly increase of M1 macrophages. However, macrophage deletion of Lpcat3 in (LDL receptor) Ldlr KO mice, both male and female, on a Western type diet, did not have a significant impact on atherogenesis. In conclusion, LPCAT3 is one of LPCATs in macrophages, involved in PC remodeling. LPCAT3 deficiency has no effect on cholesterol efflux. However, the deficiency promotes macrophage inflammatory response, but such an effect has a marginal influence on the development of atherosclerosis.
Highlights
Phosphatidylcholines (PCs), the major phospholipids, on mammalian cell membrane exhibit structural diversity [1, 2]
We found that, besides lysophosphatidylcholine acyltransferase 3 (LPCAT3), LPCAT1, and LPCAT2 are Lysophosphatidylcholine acyltransferase (LPCAT) isoforms expressed in macrophages and both may play important roles in PC remodeling in the cell
We have demonstrated that depletion of the Lpcat3 in macrophages induced a significant 1) reduction of polyunsaturated PCs on cell membrane; 2) induction of M1 macrophages in peritoneal region; and 3) induction of macrophage inflammation through toll like 4 receptor (TLR4) and c-Src pathways
Summary
Phosphatidylcholines (PCs), the major phospholipids, on mammalian cell membrane exhibit structural diversity [1, 2]. Polyunsaturated PCs ensure the fluidity of cell membrane. The plasma membrane provides a platform that mediates inflammation. We found that a decrease in macrophage plasma membrane sphingomyelin level can effectively prevent inflammatory responses by reducing TLR4 expression [6,7,8], decreasing atherosclerosis [6, 7, 9]. It is reported that cellular lipids are important regulators of c-Scr activation by altering the recruitment of C-Scr to the plasma membrane [10] and many studies have shown a critical role for c-Src in macrophage-mediated inflammatory responses [11]. It is known that the composition of polyunsaturated PCs in membranes is regulated by LPCATs [12,13,14]
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