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Lipid Mediators in Life Science

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Lipid Mediators in Life Science Exp. Anim. 60(1), 7–20, 2011 —Review— Review Series: Frontiers of Model Animals for Human Diseases Lipid Mediators in Life Science Makoto MURAKAMI1, 2) 1)Biomembrane Signaling Project, The Tokyo Metropolitan Institute of Medical Science, 2–1–6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506 and 2)Department of Health Chemistry, School of Pharmaceutical Science, Showa University, 1–5–8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan Abstract: “Lipid mediators” represent a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. They are exported extracellularly, bind to their cognate G protein-coupled receptors (GPCRs) to transmit signals to target cells, and are then sequestered rapidly through specific enzymatic or non-enzymatic processes. Because of these properties, lipid mediators can be regarded as local hormones or autacoids. Unlike proteins, whose information can be readily obtained from the genome, we cannot directly read out the information of lipids from the genome since they are not genome-encoded. However, we can indirectly follow up the dynamics and functions of lipid mediators by manipulating the genes encoding a particular set of proteins that are essential for their biosynthesis (enzymes), transport (transporters), and signal transduction (receptors). Lipid mediators are involved in many physiological processes, and their dysregulations have been often linked to various diseases such as inflammation, infertility, atherosclerosis, ischemia, metabolic syndrome, and cancer. In this article, I will give an overview of the basic knowledge of various lipid mediators, and then provide an example of how research using mice, gene-manipulated for a lipid mediator-biosynthetic enzyme, contributes to life science and clinical applications. Key words: eicosanoid, knockout mouse, lipid mediator, lysophospholipid, prostaglandin Introduction non-lipidologists. These primarily arose because of the many difficulties of working with bioactive lipids, which Although it has been decades since the term “bioactive are hydrophobic (water-insoluble), unstable, structur- lipids” was broadly defined as changes in lipid levels ally variable, and typically present only in small amounts. that result in functional consequences, it has only start- Now, it has become increasingly difficult to find events ed to gain traction in the past 20 years. Now, it prom- in medical biology in which lipids do not play important, ises to occupy center stage in biological research in the if not central, roles as signaling and regulatory molecules. 21st century. This delayed recognition has its roots in Imbalance of lipid mediator signaling pathways clearly classic ideas about exclusive roles for lipids as a nutrient contributes to disease progression in inflammation, au- source of energy and as a main component of cell mem- toimmunity, allergy, cancer, atherosclerosis, hyperten- branes, which prevented general recognition of lipids by sion, metabolic syndrome, and degenerative diseases, (Received 7 May 2010 / Accepted 23 July 2010) Address corresponding: M. Murakami, Biomembrane Signaling Project, The Tokyo Metropolitan Institute of Medical Science, 2–1–6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan 8 M. MURAKAMI among others. In this article, I will provide an overview tively, were identified. In 1982, Samuelsson and Berg- of the classification and roles of various lipid mediators, strom (Sweden) who had discovered PGs and LTs, and such as eicosanoids, lysophospholipids, sphingolipids, Vane (UK) who had found that aspirin exerts its anti- and endocannabinoids. In the latter part, I will focus on inflammatory action through inhibiting COX, were a particular enzyme that produces the most intensively awarded the Nobel Prize. Thousands of studies involv- studied lipid mediator, PGE2. On the bases of cell bio- ing biochemical, pharmacological and gene knockout logical and clinical studies, together with recent analyses strategies have delineated the regulatory actions of in- of mice with manipulation of its gene, PGE2 synthase dividual PGs, LTs and other related eicosanoids in a wide (PGES) now attracts much attention as a potential target variety of physiological and pathological systems, and for a new class of anti-inflammatory, analgesic and anti- many compounds that can block the eicosanoid pathway cancer drugs which are currently being developed. are currently in clinical use. The major eicosanoid path- ways are illustrated in Fig. 1. Lipid Mediators So far, five major bioactive prostanoids that act on their cognate GPCRs, namely PGE2, PGD2, PGF2α, PGI2 Lipid mediators can be historically and structurally and thromboxane A2 (TXA2), are known. They are pro- grouped into three categories. Class 1 includes well- duced through three sequential enzymatic steps: release known arachidonic acid (AA)-derived eicosanoids in- of AA from membrane glycerophospholipids by various cluding prostaglandins (PGs), leukotrienes (LTs) and phospholipase A2 (PLA2) subtypes, oxygenated conver- their relatives [4, 56]. Class 2 includes lysophospholip- sion of AA to PGG2 and then to PGH2 by either constitu- ids or their derivatives such as platelet-activating factor tive COX-1 or inducible COX-2, and finally isomeriza- (PAF), lysophosphatidic acid (LPA) and sphingosine-1- tion of PGH2 to individual bioactive prostanoids by phosphate (S1P), which possess either glycerol or sphin- specific terminal PG synthases [56]. On the basis of gosine backbone [9, 21, 78]. Endocannabinoids can also analyses of mice gene-manipulated for the biosynthetic be categorized in this class, since the hallmark endocan- enzymes and receptors, together with pharmacological nabinoid, 2-arachidonoyl-glycerol, has a glycerol back- studies using enzyme inhibitors and receptor agonists/ bone and since endocannabinoid receptors cluster in antagonists, many physiological and pathological func- close proximity to lysophospholipid receptors on the tions have been assigned to each prostanoid. For in- phylogenetic tree [11]. Class 3 represents newly identi- stance, sleep, allergy and adiposity are regulated by fied anti-inflammatory lipid mediators derived fromω -3 PGD2, parturition and fibrosis by PGF2α, anti-thrombo- polyunsaturated fatty acids (PUFAs), such as resolvins sis and arthritis by PGI2, and thrombosis and atheroscle- [derived from eicosapentaenoic acid (EPA)] and protec- rosis by TXA2. PGE2 is the most pleiotropic prostanoid tins [derived from docosahexaenoic acid (DHA)] [2], that is produced by a variety of cell types and controls whose biosynthetic enzymes and receptors are not yet many pathological events, such as inflammation, fever, fully understood. In addition, given the recent findings pain, and cancer, through its receptors EP1 to EP4 [76]. of a few unique GPCRs that recognize medium- to long- Aspirin and related non-steroidal anti-inflammatory chain fatty acids [75], it is conceivable that some nutri- drugs (NSAIDs), which inhibit COX enzymes and ent lipids abundantly present in the circulation or tissues thereby shut off the synthesis of all prostanoids, are could exhibit lipid mediator-like actions and be regard- among the most commonly used drugs worldwide. How- ed as another class of lipid mediators. ever, since one prostanoid often counteracts another, blocking a specific prostanoid pathway, rather than mul- Class 1: eicosanoids tiple pathways altogether, would provide a more effica- It was about half a century ago when the first (or clas- cious strategy for drug development. For instance, sical) class of lipid mediators, eicosanoids (PGs and PGD2, a major prostanoid produced by mast cells, exerts LTs), which are produced from AA via the cyclooxyge- its pro-allergic action through the two receptors DP1 and nase (COX) and lipoxygenase (LOX) pathways, respec- DP2 [46], whereas PGE2 produced from stromal cells OVERVIEW OF LIPID medIAtoRS 9 Fig. 1. Lipid mediator pathways. PLA2 hydrolyzes membrane phospholipids to liberate PUFAs (e.g., arachidonic acid, EPA, and DHA) and lysophospholipids (e.g., LPC). Of approximately 30 members of the PLA2 fam- 2+ ily, cytosolic Ca -dependent PLA2 (cPLA2) is responsible for the release of arachidonic acid in a wide va- 2+ riety of cells. Some Ca -independent PLA2 (iPLA2) and secreted PLA2 (sPLA2) enzymes can also participate in the release of PUFAs and LPC in cell type- and stimulus-specific manners. In the COX pathway, arachi- donic acid is converted to PGH2 by COX-1 or COX-2 and then to bioactive prostanoids (PGD2, PGE2, PGF2α, PGI2 and TXA2) by various terminal PG synthases: hematopoietic and lipocalin-type PGD synthases (H- and L-PGDS), cytosolic and membrane-bound PGE synthases (cPGES, mPGES-1 and mPGES-2), PGF synthase, PGI synthase and TX synthase. In the 5-LOX pathway, arachidonic acid is converted to LTA4 by 5-LOX and FLAP and then to bioactive LTs by LTA4 hydrolase (LTA4H) or LTC4 synthase (LTC4S) (5-LOX path- way). Arachidonic acid, EPA and DHA are converted by 5-LOX and 12-LOX to the anti-inflammatory lipid mediators lipoxin A4 (LXA4), resolving E1 (RevE1) and protectin D1 (PD1). LPC is converted to PAF by LPCAT2 or to LPA by autotaxin. Individual lipid mediators thus produced act on their cognate GPCRs on the target cell membrane. exerts an anti-allergic action through EP3 [36]. Accord- release by PLA2, metabolism of AA to LTA4 by 5-LOX ingly, application of NSAIDs, which block both the pro- in concert with 5-LOX activating protein (FLAP), and allergic PGD2 and anti-allergic
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