Structural and functional roles of ether lipids

Ether lipids, such as plasmalogens, are peroxisomederived 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.     

The ins and outs of CD1 molecules: bringing lipids under immunological surveillance

An emerging area of investigation is the role of lipids as immunological antigens. CD1 glycoproteins comprise a family of molecules that are specialized for presenting lipids, glycolipids and lipopeptides to T lymphocytes. Variations in the cytoplasmic tail sequences of CD1 isoforms lead to differential association with adaptor proteins and consequently divergent routes of intracellular trafficking, resulting in surveillance of distinct cellular sites for binding lipid antigens. CD1 molecules efficiently gain access to lipids from intracellular microbial pathogens in endosomal compartments, and the trafficking and lipid-binding specialization of CD1 isoforms may correlate with the endosomal segregation of structurally distinct lipids. Endosomal trafficking is also critical for CD1d molecules to load antigenic self-lipids that are presented to autoreactive CD1d-restricted natural killer (NK)T cells and is required for the positive selection of these unique T cells. Recent studies reveal a key role for accessory proteins that facilitate the uptake of lipid antigens by CD1 molecules. These include lysosomal lipid-transfer proteins, such as the saposins, and apolipoprotein E, the major serum factor that binds and delivers extracellular lipids to antigen-presenting cells. These advances in understanding the CD1 lipid antigen presentation system raise new considerations about the role of the immune response in lipid-related diseases.     

Cracking the membrane lipid code

Why has nature acquired such a huge lipid repertoire? Although it would be theoretically possible to make a lipid bilayer fulfilling barrier functions with only one glycerophospholipid, there are diverse and numerous different lipid species. Lipids are heterogeneously distributed across the evolutionary tree with lipidomes evolving in parallel to organismal complexity. Moreover, lipids are different between organs and tissues and even within the same cell, different organelles have characteristic lipid signatures. At the molecular level, membranes are asymmetric and laterally heterogeneous. This lipid asymmetry at different scales indicates that these molecules may play very specific molecular functions in biology. Some of these roles have been recently uncovered: lipids have been shown to be essential in processes such as hypoxia and ferroptosis or in protein sorting and trafficking but many of them remain still unknown. In this review we will discuss the importance of understanding lipid diversity in biology across scales and we will share a toolbox with some of the emerging technologies that are helping us to uncover new lipid molecular functions in cell biology and, step by step, crack the membrane lipid code.     

Lipid metabolism in Giardia: a post-genomic perspective

Giardia lamblia, a protozoan parasite, infects a wide variety of vertebrates, including humans. Studies indicate that this anaerobic protist possesses a limited ability to synthesize lipid molecules de novo and depends on supplies from its environment for growth and differentiation. It has been suggested that most lipids and fatty acids are taken up by endocytic and non-endocytic pathways and are used by Giardia for energy production and membrane/organelle biosynthesis. The purpose of this article is to provide an update on recent progress in the field of lipid research of this parasite and the validation of lipid metabolic pathways through recent genomic information. Based on current cellular, biochemical and genomic data, a comprehensive pathway has been proposed to facilitate our understanding of lipid and fatty acid metabolism/syntheses in this waterborne pathogen. We envision that the current review will be helpful in identifying targets from the pathways that could be used to design novel therapies to control giardiasis and related diseases.     

In situ synthesis of artificial lipids

Lipids constitute one of the most enigmatic family of biological molecules. Although the importance of lipids as basic units of compartmental structure and energy storage is well-acknowledged, deciphering the biosynthesis and precise roles of specific lipid species has been challenging. To better understand the structure and function of these biomolecules, there is a burgeoning interest in developing strategies to produce noncanonical lipids in a controlled manner. This review covers recent advances in the area of in situ generation of synthetic lipids. Specifically, we report several approaches that constitute a powerful toolbox for achieving noncanonical lipid synthesis. We describe how these methodologies enable the direct construction of synthetic lipids, helping to address fundamental questions related to the cell biology of lipid biosynthesis, trafficking, and signaling. We envision that highlighting the current advances in artificial lipid synthesis will pave the way for broader interest into this emerging class of biomimetic molecules.     

Role of membrane organization and membrane domains in endocytic lipid trafficking

Lipid compositions vary greatly among organelles, and specific sorting mechanisms are required to establish and maintain these distinct compositions. In this review, we discuss how the biophysical properties of the membrane bilayer and the chemistry of individual lipid molecules play a role in the intracellular trafficking of the lipids themselves, as well as influencing the trafficking of transmembrane proteins. The large diversity of lipid head groups and acyl chains lead to a variety of weak interactions, such as ionic and hydrogen bonding at the lipid/water interfacial region, hydrophobic interactions, and van-der-Waals interactions based on packing density. In simple model bilayers, these weak interactions can lead to large-scale phase separations, but in more complex mixtures, which mimic cell membranes, such phase separations are not observed. Nevertheless, there is growing evidence that domains (i.e., localized regions with non-random lipid compositions) exist in biological membranes, and it is likely that the formation of these domains are based on interactions similar to those that lead to phase separations in model systems. Sorting of lipids appears to be based in part on the inclusion or exclusion of certain types of lipids in vesicles or tubules as they bud from membrane organelles.     

How T lymphocytes recognize lipid antigens

Recognition of lipid antigens by T lymphocytes is well established. Lipids are recognized by T cells when presented in association with CD1 antigen-presenting molecules. Both microbial and self lipids stimulate specific T lymphocytes, thus participating in immune reactions during infections and autoimmune diseases. The immune system uses a variety of strategies to solubilise lipid antigens, to facilitate their internalization, processing, and loading on CD1 molecules. Recent studies in the field of lipid antigen presentation have revealed new mechanisms which allow the immune system to sense lipids as stimulatory antigens.     

Main lipid classes in some species of deep-sea corals in the Newfoundland and Labrador region (Northwest Atlantic Ocean)

Corals contain large quantities of lipids in their tissues; these lipids may be either structural or for storage. Little information is available about the lipid content of deep-sea corals, as well as ratios of main lipid classes. In this study, lipid percentages of 81 deep-sea specimens were measured and the presence of six major classes, including sterols (STEROLS), free fatty acids (FFA), triacylglycerols (TG), monoalkyldiacyl glycerol (MADAG), wax (WAX), and sterol esters (SE), was assessed. Deep-sea corals had fewer lipids than their shallow water counterparts. Decision-tree analysis revealed a link between coral groups and total lipid percentages, showing that species within the same group were characterized by similar lipid amounts. Depth did not seem to impact the total lipid percentages, suggesting that deep-sea corals adapt to the differential access to food by changing the proportion of lipid classes while maintaining equivalent lipid levels. In deep-sea species, similar to their shallow water counterparts, energy seems to be stored as neutral lipids (wax esters and triacylglycerols), with the notable difference that a high proportion of MADAG is present. These compounds are less rich in energy than TG. Depth trends were found for FFA, TG and SE with an increase in percentages after 800 m suggesting a potential need for storage due to decreased food availability. A subsequent decrease after 1,100 m was observed for FFA and TG but a more detailed investigation is warranted as the number of specimens acquired from these depths was less than 20. It is nonetheless a surprising result as increased storage is expected when food sources are sparse.     

Apoptosis-induced changes in mitochondrial lipids

Apoptosis is an active and tightly regulated form of cell death, which can also be considered a stress-induced process of cellular communication. Recent studies reveal that the lipid network within cells is involved in the regulation and propagation of death signalling. Despite the vast growth of our current knowledge on apoptosis, little is known of the specific role played by lipid molecules in the central event of apoptosis—the piercing of mitochondrial membranes. Here we review the information regarding changes in mitochondrial lipids that are associated with apoptosis and discuss whether they may be involved in the permeabilization of mitochondria to release their apoptogenic factors, or just lie downstream of this permeabilization leading to the amplification of caspase activation. We focus on the earliest changes that physiological apoptosis induces in mitochondrial membranes, which may derive from an upstream alteration of phospholipid metabolism that reverberates on the mitochondrial re-modelling of their characteristic lipid, cardiolipin. Hopefully, this review will lead to an increased understanding of the role of mitochondrial lipids in apoptosis and also help revealing new stress sensing mechanisms in cells. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.     

Polar lipids of 'Pseudomonas diazotrophicus'

Abstract Reference strains of ' Pseudomonas diazotrophicus ' produce a range of polar lipids atypical of authentic Pseudomonas species. In addition to the phospholipids common in Gram-negative bacteria (phosphatidylglycerol, diphosphatidylglycerol, and phosphatidylethanolamine), N -methylated derivatives of phosphatidylethanolamine (including phosphatidylcholine) and an ornithine amide lipid are also present. The preponderant ester-bound fatty acid (up to 80% of the total) is cis -vaccenic acid ( cis -octadec-11-enoic acid), while 3-hydroxyoctadecanoic acid is the major amide-bound fatty acid in the ornithine lipid. Possible implications of the data for classification of the organism are discussed.     

Old and new generation lipid mediators in acute inflammation and resolution

Originally regarded as just membrane constituents and energy storing molecules, lipids are now recognised as potent signalling molecules that regulate a multitude of cellular responses via receptor-mediated pathways, including cell growth and death, and inflammation/infection. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. The diversity of their actions arises because such metabolites are synthesised via discrete enzymatic pathways and because they elicit their response via different receptors. This review will collate the bioactive lipid research to date and summarise the findings in terms of the major pathways involved in their biosynthesis and their role in inflammation and its resolution. It will include lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins and maresins).     

Effects of diet and development on the Drosophila lipidome

Cells produce tens of thousands of different lipid species, but the importance of this complexity in vivo is unclear. Analysis of individual tissues and cell types has revealed differences in abundance of individual lipid species, but there has been no comprehensive study comparing tissue lipidomes within a single developing organism. Here, we used quantitative shotgun profiling by high‐resolution mass spectrometry to determine the absolute (molar) content of 250 species of 14 major lipid classes in 6 tissues of animals at 27 developmental stages raised on 4 different diets. Comparing these lipidomes revealed unexpected insights into lipid metabolism. Surprisingly, the fatty acids present in dietary lipids directly influence tissue phospholipid composition throughout the animal. Furthermore, Drosophila differentially regulates uptake, mobilization and tissue accumulation of specific sterols, and undergoes unsuspected shifts in fat metabolism during larval and pupal development. Finally, we observed striking differences between tissue lipidomes that are conserved between phyla. This study provides a comprehensive, quantitative and expandable resource for further pharmacological and genetic studies of metabolic disorders and molecular mechanisms underlying dietary response.     

Molecular breeding strategies for the modification of lipid composition

Summary Lipids are key components of all living cells. Acyl lipids and sterols provide the matrix of the biological membranes that both define the boundaries of cells and organelles, and act as sites for the trafficking of molecules within and into/out of cells. Lipids are also important metabolic intermediates and the most efficient form of energy storage that is available to a cell. It is the latter, energy-storing function that is of most relevance to this review. Storage lipids are accumulated in abundance in many of our most important crops, including maize, soybean, rapeseed, and oil palm, giving rise to a commerical sector valued at over $50 billion/year. Because the storage lipids of the major global oil crops have a relatively restricted composition, there is great interest in using all available breeding technologies, whether traditional or modern, to enhance the variation in lipid quality in existing crops and/or to domesticate new crops that already accumulate useful novel lipids. Over the past few decades, there has been a great deal of effort to manipulate fatty acid composition in order to produce novel lipids, especially for industrial applications. However, these attempts, many based on genetic engineering, have met with only limited commercial success-to date. More recently, there has been a resurgence of interest in the modification of both acyl and non-acyl lipids to enhance the nutritional quality of plant oils. In this review, we will examine the background to plant lipid modification and some of the latest developments, with a particular focus on edible oils.     

Lipid mimetics: A versatile toolbox for lipid biology and beyond

Being the principal component of biological membranes lipids are essential building blocks of life. Given their huge biological importance, the investigation of lipids, their properties, interactions and metabolic pathways is of prime importance for the fundamental understanding of living cells and organisms as well as the emergence of diseases. Different strategies have been applied to investigate lipid-mediated biological processes, one of them being the use of lipid mimetics. They structurally resemble their natural counterparts but are equipped with functionality that can be used to probe or manipulate lipid-mediated biological processes and biomembranes. Lipid mimetics therefore constitute an indispensable toolbox for lipid biology and membrane research but also beyond for potential applications in medicine or synthetic biology. Herein, we highlight recent advances in the development and application of lipid-mimicking compounds.     

Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry in lipid and phospholipid research

The interest in the analysis of lipids and phospholipids is continuously increasing due to the importance of these molecules in biochemistry (e.g. in the context of biomembranes and lipid second messengers) as well as in industry. Unfortunately, commonly used methods of lipid analysis are often time-consuming and tedious because they include previous separation and/or derivatization steps. With the development of "soft-ionization techniques" like electrospray ionization (ESI) or matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF), mass spectrometry became also applicable to lipid analysis. The aim of this review is to summarize so far available experiences in MALDI-TOF mass spectrometric analysis of lipids. It will be shown that MALDI-TOF MS can be applied to all known lipid classes and the characteristics of individual lipids will be discussed. Additionally, some selected applications in medicine and biology, e.g. mixture analysis, cell and tissue analysis and the determination of enzyme activities will be described. Advantages and disadvantages of MALDI-TOF MS in comparison to other established lipid analysis methods will be also discussed.     

Reign in the membrane: How common lipids govern mitochondrial function

The lipids that make up biological membranes tend to be the forgotten molecules of cell biology. The paucity of data on these important entities likely reflects the difficulties of studying and understanding their biological roles, rather than revealing a lack of importance. Indeed, the lipid composition of biological membranes has a profound impact on a diverse array of cellular processes. The focus of this review is on the effects of different lipid classes on the function of mitochondria, particularly bioenergetics, in health and disease.     

The complex life of simple sphingolipids

The extensive diversity of membrane lipids is rarely appreciated by cell and molecular biologists. Although most researchers are familiar with the three main classes of lipids in animal cell membranes, few realize the enormous combinatorial structural diversity that exists within each lipid class, a diversity that enables functional specialization of lipids. In this brief review, we focus on one class of membrane lipids, the sphingolipids, which until not long ago were thought by many to be little more than structural components of biological membranes. Recent studies have placed sphingolipids-including ceramide, sphingosine and sphingosine-1-phosphate-at the centre of a number of important biological processes, specifically in signal transduction pathways, in which their levels change in a highly regulated temporal and spatial manner. We outline exciting progress in the biochemistry and cell biology of sphingolipids and focus on their functional diversity. This should set the conceptual and experimental framework that will eventually lead to a fully integrated and comprehensive model of the functions of specific sphingolipids in regulating defined aspects of cell physiology.     

Crossing the lipid divide

Archaeal membrane lipids are structurally different from bacterial and eukaryotic membrane lipids, but little is known about the enzymes involved in their synthesis. In a recent study, Exterkate et al. identified and characterized a cardiolipin synthase from the archaeon Methanospirillum hungatei. This enzyme can synthesize archaeal, bacterial, and mixed archaeal/bacterial cardiolipin species from a wide variety of substrates, some of which are not even naturally occurring. This discovery could revolutionize synthetic lipid biology, being used to construct a variety of lipids with nonnatural head groups and mixed archaeal/bacterial hydrophobic chains.     

Sphingomyelin and derivatives as cellular signals.

This comprehensive review was necessitated by recent observations suggesting that sphingomyelin and derivatives may serve second messenger functions. It has attempted to remain true to the theme of cellular signalling. Hence, it has focussed on the lipids involved primarily with respect to their metabolism and properties in mammalian systems. The enzymology involved has been emphasized. An attempt was made to define directions in which signals may be flowing. However, the evidence presented to date is insufficient to conclusively designate the mechanisms of stimulated lipid metabolism. Hence, the proposed pathways must be viewed as preliminary. Further, the biologic functions of these lipids is for the most part uncertain. Thus, it is difficult to presently integrate this sphingomyelin pathway into the greater realm of cell biology. Nevertheless, the present evidence appears to suggest that a sphingomyelin pathway is likely to possess important bioregulatory functions. Hopefully, interest in this novel pathway will grow and allow a more complete understanding of the roles of these sphingolipids in physiology and pathology.