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Phosphatidylcholines (PCs) are major phospholipids in the mammalian cell membrane. Structural remodeling of PCs is associated with many biological processes. Lysophosphatidylcholine acyltransferase 3 (Lpcat3), which catalyzes the incorporation of polyunsaturated fatty acyl chains into the sn-2 site of PCs, plays an important role in maintaining plasma membrane fluidity. Adipose tissue is one of the main distribution organs of Lpcat3, while the relationship between Lpcat3 and adipose tissue dysfunction during overexpansion remains unknown. In this study, we reveal that both polyunsaturated PC content and Lpcat3 expression are increased in abdominal adipose tissues of high-fat diet-fed mice when compared with chow-diet-fed mice, indicating that Lpcat3 is involved in adipose tissue overexpansion and dysfunction. Our experiments in 3T3-L1 adipocytes show that inhibition of Lpcat3 does not change triglyceride accumulation but increases palmitic acid-induced inflammation and lipolysis. Conversely, Lpcat3 overexpression exhibits anti-inflammatory and anti-lipolytic effects. Furthermore, mechanistic studies demonstrate that Lpcat3 deficiency promotes reactive oxygen species (ROS) generation by increasing NOX enzyme activity by facilitating the translocation of NOX4 to lipid rafts, thereby aggregating 3T3-L1 adipocyte inflammation induced by palmitic acid. Moreover, overexpression of Lpcat3 exhibits the opposite effects. These findings suggest that Lpcat3 protects adipocytes from inflammation during adipose tissue overexpansion by reducing ROS generation. In conclusion, our study demonstrates that Lpcat3 deficiency promotes palmitic acid-induced inflammation in 3T3-L1 adipocytes by enhancing ROS generation.

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.

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.

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 (Lpcat3KO Mac ). 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, Lpcat3KO Mac 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. Lpcat3KO Mac 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., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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.