Human Lysophosphatidylcholine Acyltransferases 1 and 2 Are Located in Lipid Droplets Where They Catalyze the Formation of Phosphatidylcholine

Abstract

Phosphatidylcholine (PC) is synthesized by two different pathways, the Lands cycle and the Kennedy pathway. The recently identified key enzymes of the Lands cycle, lysophosphatidylcholine acyltransferase 1 and 2 (LPCAT1 and -2), were reported to localize to the endoplasmic reticulum and to function in lung surfactant production and in inflammation response. Here, we show in various mammalian cell lines that both enzymes additionally localize to lipid droplets (LDs), which consist of a core of neutral lipids surrounded by a monolayer of phospholipid, mainly PC. This dual localization is enabled by the monotopic topology of these enzymes demonstrated in this study. Furthermore, we show that LDs have the ability to locally synthesize PC and that this activity correlates with the LPCAT1 and -2 expression level. This suggests that LPCAT1 and -2 have, in addition to their known function in specialized cells, a ubiquitous role in LD-associated lipid metabolism.

Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading

“…6 ). The effect of CE on lyso-PC metabolism could be due to the association of LPCAT enzymes to lipid droplets ( 50 ). It has been recently described that LPCAT1 knockdown induces an increase in lipid droplet size ( 50 ).…”

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

“…Even more intriguing is the idea that the local synthesis of phosphatidylcholine could enable the rapid growth of the phospholipid monolayer to keep up with an expanding hydrophobic core when TG synthesis rate is high. The role of ACSL3 would be to provide activated fatty acids for the synthesis of PC by lyso-PC acyltransferases, which have recently been shown to be partially localized to LDs ( 42 ). When cellular ACSL activity is inhibited pharmacologically, LDs decrease in size and number ( 20 ).…”

“…ACSL3 is the second most abundant protein on LDs prepared from human A431 cells ( 42 ). Therefore, we chose this cell model to analyze the functional consequences of a reduced amount of ACSL3.…”

The proteomics of lipid droplets: structure, dynamics, and functions of the organelle conserved from bacteria to humans

“…Some of these enzymes have then been localized to lipid droplets in living cells using GFP fusion proteins and immunofl uorescence ( 16,76,77 ). Several in vitro studies have verifi ed both the presence and activity of these enzymes on lipid droplets (78)(79)(80), suggesting that the lipid droplet is a cellular site for some steps of lipid synthesis.…”