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Lipid Players of Cellular Senescence

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Lipid Players of Cellular Senescence H OH metabolites OH Review Lipid Players of Cellular Senescence Alec Millner and G. Ekin Atilla-Gokcumen * Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY 14260, USA; alecmill@buffalo.edu * Correspondence: ekinatil@buffalo.edu; Tel.: +1-716-6454130 Received: 3 August 2020; Accepted: 19 August 2020; Published: 21 August 2020 Abstract: Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes. Keywords: lipids; senescence; sphingolipids; fatty acids; glycerolipids 1. Introduction Lipid Diversity and Function Organisms contain thousands of distinct lipid molecules with diverse functions in fundamental cellular processes. This diversity is achieved through the incorporation of one or multiple aliphatic chain(s), which can vary in length and unsaturation, to different polar backbones or headgroups [1] via the coordinated action of a network of enzymes that synthesize, metabolize, and transport lipids [2]. The lipid content of mammalian cells is classified into different groups, including fatty acids, glycerolipids, phospholipids, sphingolipids, and sterols [1]. Lipids have three general functions, all of which are crucial for cell survival and homeostasis [1]. First, polar lipids, with their amphipathic nature, form the cellular membranes. The hydrophobic moieties self-associate while the hydrophilic head groups interact with the aqueous environment. This phenomenon also allows compartmentalization of organelles within the cell, enabling segregation of chemical reactions and improving efficiency of biochemical pathways (Figure1A) [ 3]. The plasma membrane is primarily composed of phospholipids, cholesterol, and glycolipids. The length and unsaturation of the fatty acyl tails directly influences the fluidity of the membrane by affecting how closely the molecules can pack against each other and other biomolecules [4]. The composition of the lipid bilayer also has a profound effect on the interaction and function of membrane proteins [5]. Local lipid composition of the plasma membrane is also critical for the recruitment of certain proteins to these sites, mainly utilizing hydrophobic and electrostatic interactions [6]. Metabolites 2020, 10, 339; doi:10.3390/metabo10090339 www.mdpi.com/journal/metabolites Metabolites 2020, 10, 339 2 of 17 Metabolites 2020, 10, x FOR PEER REVIEW 2 of 18 recruitmentSecond, neutralof certain lipids proteins such asto cholesterolthese sites, estersmainly and utilizing triacylglycerols hydrophobic are mainlyand electrostatic used for storing excessinteractions fatty acids.[6]. These molecules reside within lipid droplets, endoplasmic reticulum-derived organelles,Second, and neutral provide lipids buildingsuch as cholesterol blocks foresters membranes and triacylglycerols or substrates are mainly for used energy for storing metabolism (Figureexcess1 B)fatty [ 7acids.]. The These biogenesis molecules of reside lipid within droplets lipid is droplets, activated endoplasmic at high intracellular reticulum-derived lipid levels, resultingorganelles in, the and production provide building of these blocks cytosolic for membranes organelles or substrates that are composed for energy ofmetabolism a neutral ( lipidFigure core and enclosed1B) [7]. withThe biogenesis a phospholipid of lipid monolayerdroplets is activated [7]. at high intracellular lipid levels, resulting in the production of these cytosolic organelles that are composed of a neutral lipid core and enclosed with Lastly, lipids and their metabolites can trigger numerous physiological responses and are a phospholipid monolayer [7]. involvedLastly, in many lipids fundamental and their metabolites cellular processes. can trigger They numerous can bind physiological to various proteins, responses activate and are signaling cascades,involved and in many elicit afundamental specific cellular cellular response. processes. One They such can example bind to isvarious the binding proteins, of activate diacylglycerol (DAG)signaling to proteincascades, kinase and elicit C, whicha specific can cellular affect aresponse. broad rangeOne such of cellular example programs is the binding and adhesion,of migration,diacylglycerol and proliferation(DAG) to protein (Figure kinase1C) C, [which8,9]. Hydrolysiscan affect a broad of phosphatidylinositol range of cellular programs 4,5-bisphosphate and releasesadhesion, inositol-1,4,5-trisphosphate migration, and proliferation and (Figure DAG 1C) (Figure [8,9]. 2HydrolysisA). DAG actsof phosphat as an allostericidylinositol activator 4,5- of proteinbisphosphate kinase C,releases and inositol-1,4,5-trisphosphate inositol-1,4,5-trisphosphate and binds DAG to ( calciumFigure 2A channels,). DAG acts modulating as an allosteric intracellular calciumactivator [10 of]. Spikesprotein inkinase calcium C, and mediate inositol the-1,4,5 localization-trisphosphate of protein binds to kinase calcium C to channels, membranes modulating with DAG [11]. Uponintracellular recruitment calcium to the[10] membrane,. Spikes in calcium protein mediate kinase Cthe is activatedlocalization and of undergoesprotein kinase conformational C to membranes with DAG [11]. Upon recruitment to the membrane, protein kinase C is activated and changes, exposing DAG binding sites [12,13]. This signaling cascade is critical for cellular homeostasis; undergoes conformational changes, exposing DAG binding sites [12,13]. This signaling cascade is hence,critical dysregulation for cellular homeostasis of DAG-dependent; hence, dysregulation protein kinase of DAG C-dependent activity has protein been kinase implicated C activity in various diseaseshas been including implicated cancer in various [14] anddiseases cardiac including disease cancer [15]. [14] and cardiac disease [15]. FigureFigure 1. 1.Di Differentfferent roles of of lipids. lipids. (A ()A Phosphatidylcholine) Phosphatidylcholine and cholesterol and cholesterol are major are structura major structurall lipids. lipids. (B()B) Cholesterol Cholesterol estersesters and triacylglycerols triacylglycerols are are used used to stored to stored excess excess fatty fattyacids acidsin cells. in They cells. are They stored are stored withinwithin lipid lipid droplets and and endoplasmic endoplasmic reticulum reticulum-derived-derived vesicular vesicular structures. structures. (C) Diacylglycerol (C) Diacylglycerol and sphingosine-1-phosphate are signaling lipids. Diacylglycerols affect protein kinase C activity, and and sphingosine-1-phosphate are signaling lipids. Diacylglycerols affect protein kinase C activity, sphingosine-1-phosphate promotes proliferation through its interactions with cell surface receptors. and sphingosine-1-phosphate promotes proliferation through its interactions with cell surface receptors. Sphingolipids also act as highly bioactive signaling molecules [16]. Accumulation of ceramides Sphingolipids also act as highly bioactive signaling molecules [16]. Accumulation of ceramides and sphingosine can lead to an anti-proliferative or pro-apoptotic response [17]. However, andsphingosine sphingosine can can instead lead be to converted an anti-proliferative to sphingosine or- pro-apoptotic1-phosphate, which response promotes [17]. cell However, growth sphingosineand canproliferation instead be ( convertedFigure 2B) to[1 sphingosine-1-phosphate,8,19]. The interplay between which different promotes sphingolipids cell growth and andhow proliferationcells (Figuremaintain2B) [a18 balanced,19]. The sphingolipid interplay between pool is dinotfferent fully sphingolipidsunderstood, but and it howis well cells-established maintain that a balanced sphingolipiddisrupted sphingolipid pool is not levels fully are understood, observed in but numerous it is well-established diseases [16,20]. that Similar disrupted to the pro sphingolipid-death and levels aresurvival observed roles in of numerous different sphingolipids, diseases [16 the,20 ].products Similar of to arachidonic the pro-death acid in and the survivaleicosanoid roles pathway of di fferent sphingolipids,can exhibit opposing the products bioactivities. of arachidonic Prostaglandin acid E2 in (PGE2) the eicosanoid has an immunosuppressive
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