Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport

Abstract

Polyunsaturated fatty acids (PUFAs) in phospholipids affect the physical properties of membranes, but it is unclear which biological processes are influenced by their regulation. For example, the functions of membrane arachidonate that are independent of a precursor role for eicosanoid synthesis remain largely unknown. Here, we show that the lack of lysophosphatidylcholine acyltransferase 3 (LPCAT3) leads to drastic reductions in membrane arachidonate levels, and that LPCAT3-deficient mice are neonatally lethal due to an extensive triacylglycerol (TG) accumulation and dysfunction in enterocytes. We found that high levels of PUFAs in membranes enable TGs to locally cluster in high density, and that this clustering promotes efficient TG transfer. We propose a model of local arachidonate enrichment by LPCAT3 to generate a distinct pool of TG in membranes, which is required for normal directionality of TG transfer and lipoprotein assembly in the liver and enterocytes.DOI: http://dx.doi.org/10.7554/eLife.06328.001

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

“…4, A and B) could explain the compensation for defective cholesterol uptake in Lpcat3-deficient enterocytes. It has been shown that global deletion of Lpcat3 at an early stage of development results in the accumulation of lipid droplets in enterocytes (9,10). However, we did not find any difference in lipid levels in the small intestine of Lpcat3-deficient and control mice (Fig.…”

“…It has been reported that ablation of Lpcat3 reduces arachidonoyl-PCs in the embryonic and postnatal small intestine (9,10). We found that Lpcat3 deficiency in the small intestine significantly decreased polyunsaturated PCs, including 16:0/18:2, 18:1/18:2, 18:1/18:3, and 18:0/20:4 (Table 1), and this modification could disrupt the structural integrity and fluidity of the plasma membrane.…”

“…Does Lpcat3 deficiency affect lipid secretion? Based on studies of the small intestine in neonatal mice, two groups of researchers proposed models for the assembly of Lpcat3-related apoB-containing lipoproteins (9,10). However, cholesterol secretion in cultured primary enterocytes is mediated by both apoB-dependent and -independent pathways (14).…”

“…Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9,10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9).…”

ER Membrane Phospholipids and Surface Tension Control Cellular Lipid Droplet Formation

“…Another example, which is extreme, is the formation of lipoprotein particles, which are particular forms of LDs made in the ER lumen. The budding of triglyceride-containing lipoproteins requires the local production of polyunsaturated phospholipids by LPCAT3 (Hashidate-Yoshida et al, 2015). We have found that these phospholipids specially allowed the budding of triglyceride droplets ( Figure 2E).…”