Structural and functional roles of ether lipids

Abstract

Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.

Keywords: cancer; ether lipids; metabolic disorders; peroxisomes; phospholipid; plasmalogen.

Figure 1

Chemical structures of diacyl and ether-linked phospholipids. Diacyl phospholipids have fatty acyl side chains linked to the sn-1 and sn-2 position of the glycerol backbone by ester bonds. Ether-linked phospholipids are a subclass of glycerophospholipids that have an alkyl chain attached by an ether bond at the sn-1 position. The sn-2 position of ether lipids generally has an ester-linked acyl chain, as in diacyl phospholipids. Some ether-linked phospholipids, called alkenyl-acylphospholipids, contain a cis double bond adjacent to the ether linkage and are commonly referred to as plasmalogens. The polar head group of ether-linked phospholipids is most commonly choline or ethanolamine

Figure 2

Acyl-DHAP pathway of ether lipid synthesis. This process begins in peroxisomes and is subsequently completed in the ER. The pathway utilizes dihydroxyacetone phosphate (DHAP) generated by glycerol 3-phosphate dehydrogenase (G3PDH)-mediated dehydrogenation of G3P as the substrate for ether lipid synthesis. Fatty acid synthase (FAS)-mediated de novo lipogenesis generates fatty acyl-CoA that is utilized by glyceronephosphate O-acyltransferase (GNPAT) or reduced to a fatty alcohol by a fatty acyl-CoA reductase (FAR1 or FAR2) to later be catalyzed by alkylglycerone phosphate synthase (AGPS), forming the ether bond and exchanging the acyl chain for an alkyl group. PexRAP (an acyl/alkyl DHAP reductase) then catalyzes the final peroxisomal step, generating the ether lipid precursors, 1-O-alkyl-G3P (AGP) or the diacyl phospholipid precursor lysophosphatidic acid (LPA). The completion of phospholipid synthesis occurs in the ER. This includes acylation of the glycerol backbone at the sn-2 position, converting LPA to diacylglycerol (DAG) and AGP to alkyl-acylglycerol (AAG), as well as addition of a cytidine diphosphate-alcohol head group (such as CDP-choline or CDP-ethanolamine) at the sn-3 position to form the mature phospholipid

Figure 3

Peroxisomal lipid synthesis is required for maintaining neutrophil viability and membrane integrity. In healthy neutrophils, fatty acid synthase (FAS) and PexRAP participate in peroxisomal lipid synthesis, including the generation of ether-linked phospholipids that are incorporated into the plasma membrane, contributing to membrane integrity. Genetic ablation of FAS or PexRAP disrupts the lipid synthetic pathway, leading to a preferential loss of ether-linked phospholipids in neutrophils. This alters membrane stability, leading to the activation of ER stress, increased apoptosis, and ultimately neutropenia

Figure 4

Role of ether lipids in Schwann cell differentiation and myelination. In a healthy Schwann cell, the cell membrane is enriched in plasmalogens. This is necessary for proper recruitment of Akt to the plasma membrane, resulting in its phosphorylation and activation. Activated Akt phosphorylates GSK3β at Ser9, inhibiting its activity. Plasmalogen deficiency impairs recruitment and activation of Akt, preventing it ability to inhibit GSK3β. Active GSK3β impairs Schwann cell differentiation, resulting in disrupted radial sorting and myelination. Supplementation of lithium or TDZD-8 to inhibit GSK3β rescues plasmalogen-deficient phenotype, restoring differentiation and myelination