Deletion of lysophosphatidylcholine acyltransferase 3 in myeloid cells worsens hepatic steatosis after a high-fat diet

Thibaut Bourgeois,Hélène Choubley,Charlène Magnani,Thomas Gautier,David Masson,Marion Xolin,Antoine Jalil,Jacques Grober,Philippe Saas,Victoria Bergas,Laurent Lagrost,Loïc Mazzeo,Tony Jourdan,Chloé Buch,L Lebrun ,Kevin Van Dongen ,Naïg Le Guern ,Jérôme Labbé ,Jean‐Paul Pais De Barros ,Charles W Thomas ,Louise Ménégaut

doi:10.1194/jlr.ra120000737

Abstract

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.

Highlights

Phospholipids (PLs) are continuously remodeled in a succession of deacylation and reacylation reactions called the Lands cycle [1]
As compared with total Lpcat3 deficiency [12], changes in fatty acids (FAs) composition of PLs were less pronounced in Lpcat3KOMac cells, and there was no significant increase in non-esterified FA levels (Fig. 1J) including arachidonic acid (AA) and C22:4 n-6 as it was the case in Lpcat3−/− macrophages [12]
Recent studies have highlighted the major role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine with dramatic consequences on cell-membrane-associated processes such as lipid absorption, lipoprotein secretion, and SREBP cleavage [5, 6, 11]

Summary

Introduction

Phospholipids (PLs) are continuously remodeled in a succession of deacylation and reacylation reactions called the Lands cycle [1]. Each LPLAT action is tissue- and substratedependent [2, 3] One of these enzymes, the lysophosphatidylcholine acyltransferase 3 (LPCAT3), is highly expressed in the liver and the intestine and in macrophages [4,5,6]. Constitutive Lpcat deficiency is lethal few days after birth probably due to the malabsorption of dietary lipids [5, 9, 11]. While these studies focused mainly on the liver and intestine, the impact of LPCAT3 on macrophage functions is more controversial. While acute Lpcat inhibition in murine peritoneal macrophages was shown to potentiate the

Objectives

Methods

Results

Conclusion