Lipids as Bioeffectors. Introduction

E. V. Dyatlovitskaya^* and V. V. Bezuglov

Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117871 Russia; fax: (095) 335-7103; E-mail: jgmol@ibch.siobc.ras.ru

^* To whom correspondence should be addressed.

Received August 20, 1997

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In this introductory paper functions of lipids with special emphasis on their bioeffector role, which is reported in the reviews published in this issue of journal, are discussed.

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KEY WORDS: sphingolipids, phospholipids, fatty acids, oxylipins, cell signaling, lipid functions

The term "lipids" encompasses a great number of slightly polar natural compounds with various chemical structures, such as free fatty acids, neutral glycerides, waxes, phospholipids, sphingolipids (including glycosphingolipids), oxylipins, sterols, etc. For an appreciable length of time it was thought that lipids play a relatively conservative role in cell activity. They were considered mainly as metabolic fuel stores. Later, it was established that lipids also play another vital function: they are the main structural component of cell membranes [1-3]. However, the reason for the existence of such large amounts of compounds of lipid nature, which differ in chemical structure, remained unclear. Reviewing of the role of lipids in vital systems was initiated at the beginning of the 1960s, after establishing the structure, biosynthetic pathways, and physiological role of prostaglandins. During the two last decades, especially in the 1990s, many studies have shown that other lipids also act as important biological effectors, regulators, and mediators which participate in virtually all biological processes in an organism as a whole (such as immune response, transmission of neuronal information, regulation of vessel and muscle tonus, homeostasis, inflammation, etc.) and in biochemical reactions of animal and human cells. As second messengers they provide transduction of various external signals into the cell, and they simultaneously act as intercellular mediators [4-11].

By now numerous data on the bioeffector role of lipids both at the whole-body level and in a cell have been published. Some of these data are discussed in detail in this issue of Biochemistry (Moscow).

It was discovered that glycosphingolipids participate in the processes of cell growth, differentiation, and recognition, intercellular interactions, and transmembrane signal transduction (see the review of A. Futerman [12] and [13-16]). They may also act as antigens and active immunomodulators [17].

Simple sphingolipids and their metabolites (i.e., sphingenine, sphingenine-1-phosphate, and ceramides) as second messengers participate in the processes of cell growth, differentiation, and apoptosis (see the reviews of Alessenko [18], Spiegel et al. [19], Dyatlovitskaya [20], Futerman [12], and Martinova [21]).

The bioeffector role of phospholipids is well-known. For instance, in many papers it has been reported that compounds involved in the phosphatidylinositol cycle (i.e., diacylglycerol, inositol phosphate, inositol-1,4,5-trisphosphate, and phosphatidic acid), along with activation of some forms of protein kinase C and Ca²⁺ release from intracellular stores, etc., can also participate in cell signaling as second messengers (see the reviews of Tkachuk [22] and paper [7]). It was discovered that the platelet-activating factor 1-O-alkyl-2-acetylphosphatidylcholine also is a potent bioeffector that regulates many biological processes in blood (see the review of Kulikov and Muzya [23]).

Numerous data have been published recently on the regulatory role of lysophosphatidylcholine (lysolecithin), which previously was considered only as an endogenous detergent. It was shown that at low concentrations (1-10 µM) lysophosphatidylcholine activates protein kinase C, stimulates cell proliferation, differentiation of lymphocytes, etc. (see the review of Prokazova, Zvezdina, and Korotaeva [24]).

A great number of papers describes the role of polyunsaturated fatty acids and their derivatives (i.e., monoacylglycerols, amides, and oxylipins) as effectors. For instance, it was discovered that free fatty acids modulate the activity of phospholipases, ionic channels, ATPases, G-proteins, and protein kinases. They also regulate the phosphoinositide and sphingomyelin cycle, hormonal signal transduction, and gene transcription (see the review of Kogteva and Bezuglov [25]). It should be noted that the above-mentioned effects do not exhaust all regulatory potentials of fatty acids. At the same time, these effects are due to their own biological activity rather than to their preliminary oxidation, which, in turn, gives a wide range of highly active oxylipins. The latter are not stored in the cells in the ready form, but are synthesized from polyenic fatty acids in response to different biological stimuli. Due to the large variety of their effects, they participate in the regulation of the majority of normal and pathological processes in organisms (see the reviews of Petrukhina and Makarov [26] as well as of Sala, Zarini, and Bolla [27]).

It was shown that amides of fatty acids exert neuromodulatory effects. For example, ethanolamide of arachidonic acid (anandamide) may serve as an endogenous ligand for brain cannabinoid receptor, and the amide of oleic acid (oleamide) is an endogenous sleep inducer in mammals (see the review of Bezuglov, Bobrov, and Archakov [28]). These findings have opened a new chapter in the study of the bioeffector role of lipids. They demonstrated that even lipid molecules of simple structure have specific regulatory functions. This conclusion was confirmed by the demonstration of the endocannabinoid properties characteristic of 2-arachidonoylglycerol, which previously was considered only as an insignificant metabolite of di- and triacylglycerols (see the review of Di Marzo [29]).

Previously it was suggested that free-radical lipid peroxidation induced by reactive oxygen species yields products exerting only slightly specific biological effects. However, currently lipid peroxidation is considered as another route of effector molecule synthesis. For example, isoprostanes (which are analogous to prostaglandins produced in the organism as a result of free-radical lipid peroxidation) exhibit a high level of biological activity. It has been suggested that their effects are mediated by specific receptors and that isoprostanes themselves are very precise indicators of free-radical lipid peroxidation [30]. An assumption can be made that, along with isoleukotrienes [31] and other isooxylipins, isoprostanes are representative of a new class of lipid effectors which mediate oxidative stress.

Analysis of the data on the biological effects of different types of lipids indicate that the cell may be simultaneously affected by several lipid effectors. Different lipid regulators and messengers often have opposing effects on a cell. For instance, protein kinase C is activated by diacylglycerol and inhibited by sphingenine; apoptosis is potentiated by ceramides and suppressed by diacylglycerols.

Conversely, the same effect may be caused by different lipid bioregulators. For example, inositol-1,4,5-trisphosphate, sphingenine, sphingenine-1-phosphate, arachidonic acid, lysophosphatidylcholine, and 2-arachidonoylglycerol induce Ca²⁺ release; sphingenine and ceramides stimulate apoptosis, etc.

Lipid effectors often exhibit a synergistic mode of action. It was shown that lysophosphatidylcholine and free fatty acids increase diacylglycerol-stimulated activity of certain forms of protein kinase C.

It should by noted that binding of the same agonist (e.g., tumor necrosis factor, gamma-interferon. or interleukin-1beta) at the cell surface may result in a simultaneous activation of phospholipases A₂, C, and D [32] and sphingomyelinase, thus leading to arachidonic acid release, stimulation of the sphingomyelin cycle [33], phosphatidylcholine hydrolysis, and production of diacylglycerols [5, 32]. As a result, several types of lipid messengers occurring in the cell may simultaneously affect biochemical processes. For this reason, in some cases it is very difficult to reveal the key acting agent.

Finally, we should mention the "cross-talks" between different phospholipases, enzymes involved in synthesis of oxylipins, and lipid effectors, which result in the modulation of the effects of individual bioregulators and provide a precise adjustment of the biological response [7, 32].

The data presented in the reviews demonstrate that lipids are important bioeffectors essential for function of both a cell and the organism as a whole. Thus, at present it can be concluded that lipids fulfill three main functions. First, lipids are vital structural components of cell membranes. Second, lipids are important bioeffectors that regulate intracellular biochemical reactions, intercellular interactions, and various physiological processes in organisms. The third function, which for a long time was considered as the only one, is as the storage of biological fuel. Now the reason for the existence of such a variety of chemical structures of lipids is better understood, because interaction of bioeffectors with their targets and, therefore, the specificity of their effects depends on the structure of the molecule.

Studies on the regulatory role of lipids are now in progress. Probably in the nearest future new data on their effector roles will appear.

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