Phospholipid Remodeling in Physiology and Disease

Abstract

Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands' cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.

Keywords: cholesterol metabolism; intestinal homeostasis; lipid metabolism; lipogenesis; lipoprotein production; lysophosphatidylcholine acyltransferase; phospholipid remodeling; surfactant biosynthesis.

Figure 1

PC metabolism in mammalian cells. PC is synthesized de novo through the Kennedy pathway. Choline is first phosphorylated by choline kinase to generate phosphocholine, followed by the formation of CDP-choline catalyzed by CT. Finally, CDP-choline is converted into PC by CPT. In liver, PC can also be generated through the PEMT pathway in which PE is sequentially methylated by PEMT. De novo synthesized PC undergoes remodeling in a process called Lands’ cycle, which determines the acyl chain linked to PC species at the sn-2 position. Fatty acyl chains at sn-2 site of PC are hydrolyzed by PLA2s. The resulting lysoPC is reacylated by LPCATs. LPCATs catalyze the incorporation of another fatty acyl chain into the sn-2 site of lysoPC to produce a new PC species. Abbreviations: CMP, cytidine monophosphate; CPT, CDP-choline:1,2-diacylglycerol cholinephosphotransferase; CT, CTP:phosphocholine cytidylyltransferase; DAG, diacylglycerol; LPCAT, lysophosphatidylcholine acyltransferase; PC, phosphatidylcholine; PEMT, phosphatidylethanolamine N-methyltransferase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine.

Figure 2

Roles of Lpcat3 in VLDL secretion and SREBP-1c–mediated lipogenesis in liver. In wild-type mice, Lpcat3 catalyzes the incorporation of polyunsaturated fatty acids into phospholipids. Polyunsaturated phospholipids facilitate SREBP-1c transport and processing, thereby promoting lipogenesis. Increased abundance of polyunsaturated phospholipids in endoplasmic reticulum creates a dynamic membrane environment that facilitates the transfer of triglyceride to pre-VLDL, leading to the efficient lipidation of VLDL. In contrast, loss of Lpcat3 in liver reduces membrane arachidonoyl phospholipids and decreases membrane mobility and curvature, which impacts the bulk triglyceride addition to lipid-poor ApoB particles and thus produces smaller VLDL particles. Similarly, reduced membrane mobility in Lpcat3-deficient liver impairs SREBP-1c transport and processing, leading to reduced lipogenesis. Abbreviations: C, C terminus; COPII, coat protein complex II; ER, endoplasmic reticulum; KO, knockout; Lpcat, lysophosphatidylcholine acyltransferase; SCAP, sterol regulatory element-binding protein cleavage-activating protein; SRE, SREBP response element; TG, triglyceride; VLDL, very low-density lipoprotein.

Figure 3

Lpcat3 and phospholipid remodeling in lipid absorption in small intestine. Loss of LPCAT3 in intestine reduces polyunsaturated phospholipid content and membrane fluidity, impairs passive fatty acid transport across the apical membrane of enterocytes and decreases chylomicron assembly and secretion. In wild-type mice, Lpcat3 activity increases polyunsaturated phospholipid levels and membrane fluidity, which is essential for efficient fatty acid transport into enterocytes for TG synthesis and chylomicron assembly, when challenged with a bolus of lipids. Lpcat3 deficiency reduces the expression of NPC1L1 and ABCA1 in the enterocytes, which leads to decreased cholesterol absorption and cholesterol transfer to pre-β HDL to produce HDL. Abbreviations: ER, endoplasmic reticulum; HDL, high-density lipoprotein; KO, knockout; Lpcat, lysophosphatidylcholine acyltransferase; TG, triglyceride.