Fatty Acids - from Energy Substrates to Key Regulators of Cell Survival, Proliferation and Effector Function

Review www.cell-stress.com Fatty acids - from energy substrates to key regulators of cell survival, proliferation and effector function Danilo Cucchi1, Dolores Camacho-Muñoz2, Michelangelo Certo3, Valentina Pucino3, Anna Nicolaou2,4,* and Claudio Mauro3,5,6,* 1 Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. 2 Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, School of Health sciences, The University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester M13 9PT, UK. 3 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Mindelsohn Way, Birming- ham B15 2WB, UK. 4 Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester M13 9PT, UK. 5 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Mindelsohn Way, Birming- ham B15 2WB, UK. 6 Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Mindelsohn Way, Birmingham B15 2WB, UK. * Corresponding Authors: Anna Nicolaou, Stopford Building, Oxford Road, Manchester M13 9PT, UK; E-mail: [email protected]; Claudio Mauro, Queen Elizabeth Hospital, Mindelsohn Way, Birmingham B15 2WB, UK; E-mail: [email protected] ABSTRACT Recent advances in immunology and cancer research doi: 10.15698/cst2020.01.209 show that fatty acids, their metabolism and their sensing have a cru- Received originally: 07.10.2019 cial role in the biology of many different cell types. Indeed, they are in revised form: 02.12.2019, Accepted 04.12.2019, able to affect cellular behaviour with great implications for patho- Published 10.12.2019. physiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and ago- nists/antagonists that are potential therapeutic targets, some of Keywords: fatty acids; immune cells; T cells; which have already been successfully pursued. Fatty acids can affect cancer cells; metastasis; cancer immunology. the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the Abbreviatons: balance between anti- and pro-inflammatory signals in immune dis- ACC – acetyl-CoA carboxylase, ACLY – ATP citrate eases, such as rheumatoid arthritis, psoriasis, diabetes, obesity and lyase, CPT – carnitine palmitoyl transferases, CRPC – cardiovascular conditions. In the context of cancer biology, fatty ac- castration-resistant prostate cancer, DHA – docosahexaenoic acid, EAE – experimental ids mainly provide substrates for energy production, which is of cru- autoimmune encephalomyelitis, EMT – epithelial to cial importance to meet the energy demands of these highly prolif- mesenchymal transition, EPA – eicosapentaenoic erating cells. Fatty acids can also be involved in a broader transcrip- acid, FABP – Fatty acid binding protein, FADS – fatty tional programme as they trigger signals necessary for tumorigenesis acyl-CoA desaturase, FAS – fatty acid synthase, GA – gastric adenocarcinoma, HCC – hepatocellular and can confer to cancer cells the ability to migrate and generate carcinoma, HDAC – histone deacetylase, HFD – high distant metastasis. For these reasons, the study of fatty acids repre- fat diet, ILC – innate lymphoid cell, LAL – lysosomal sents a new research direction that can generate detailed insight and acid lipase, LMW-E – low molecular weight isoform provide novel tools for the understanding of immune and cancer cell of cyclin E, LPS – lipopolysaccharide, mCRPC – metastatic CRCP, NK – natural killer, PI(4,5)P2 – biology, and, more importantly, support the development of novel, phosphatidylinositol (4,5) bisphosphate, PLD – efficient and fine-tuned clinical interventions. Here, we review the phospholipase D, PPAR – peroxisome proliferator- recent literature focusing on the involvement of fatty acids in the activated receptor, PUFA – polyunsaturated fatty biology of immune cells, with emphasis on T cells, and cancer cells, acid, SCD – stearoyl-CoA desaturase, SREBP – sterol regulatory element binding protein, Tconv – from sensing and binding, to metabolism and downstream effects in conventional T cell, TCR – T cell receptor, Teff – T cell signalling. effector cell, Th – T helper cell, Tm – T memory cell, TNBC – triple-negative breast cancer, Treg – regulatory T cell, wt – wild type. OPEN ACCESS | www.cell-stress.com 9 Cell Stress | JANUARY 2020 | Vol. 4 No. 1 D. Cucchi et al. (2019) Fatty acid metabolism in immunity and cancer INTRODUCTION Of particular interest is GPR84, which has affinity for fatty Lipids are important biomolecules involved in a plethora of acyl chain length of 6-14 C (medium chain fatty acids) and biological processes, spanning from the production and is expressed by a variety of immune cells, mainly neutro- storage of energy [1] and assembly and function of the phils and monocytes/macrophages, and to a lesser extent, cellular membranes [2] to activation of genes [3] and mod- by CD4+ and CD8+ T cells. Expression of GPR84 both in hu- ulation of signalling pathways [4]. This diverse group of man and mouse monocytes is upregulated upon lipopoly- compounds comprises fatty acids, glycerolipids, glycer- saccharide (LPS) stimulation, suggesting that signals trig- ophospholipids, sphingolipids, sterol lipids, prenol lipids, gered by medium chain fatty acids may have a role in saccharolipids and polyketides [5-7]; typically, the cellular monocyte/macrophage activation [14]. Moreover, medium lipidome comprises more than 2,000 species. This structur- chain saturated fatty acids such as caproic acid (C6), un- al diversity endows lipids with varied properties that ena- decanoic acid (C11) and lauric acid (C12), are able to stimu- ble and support a plethora of structural and functional late the secretion of interleukin 12 p40 subunit (IL12 p40) roles. in mouse LPS-stimulated RAW264.7 cells, showing that As lipids are not encoded, their levels are regulated they can have a role in regulating the activity of different both by nutritional intake and biosynthetic pathways found immune cells during inflammation [14]. in almost all cell types. Fatty acids are simple lipids biosyn- It has been recently reported that the short chain fatty thesised by the complex enzyme fatty acid synthase (FAS) acids acetate (C2), propionate (C3) and butyrate (C4) are through the sequential elongation of acetyl-CoA [8]. The able to orchestrate the differentiation of CD4+ T cells in resulting 16-carbon (C) acyl chain palmitic acid can be fur- effector or regulatory cells modulating the activity of his- ther elongated and desaturated. However, humans and tone deacetylases (HDAC) [15]. Short chain fatty acids can other animals require nutritional intake of two essential also inhibit HDAC in T cells leading to the amplification of fatty acids -linoleic acid and alpha-linolenic acid - precur- the mTOR pathway, through acetylation of p70 S6 kinase sors to long and very long polyunsaturated fatty acids and consequent phosphorylation of rS6, all events required (PUFA). As well as contributing to the structural diversity of for the differentiation in T helper 17 (Th17), T helper 1 membrane glycerophospholipids and sphingolipids, PUFA (Th1) and IL-10+ T cells [15]. As short chain fatty acids can are metabolised to potent autacoids, hormone-like media- be readily uptaken through the plasma membrane [16], tors known for their involvement in inflammation and im- their effect was found to be independent of the surface munity [9-11], while the catabolism of fatty acids via β- receptors GPR41 and GPR43, which can sense acetate, oxidation provides the cells with an efficient way for ener- butyrate and propionate [17], and have been shown to be gy production. Membrane glycerophospholipids and sphin- important in regulating intestinal inflammatory responses golipids, as well as acylglycerols (e.g. triacylglycerols) act as [18]. These findings identify short chain fatty acids as cru- cellular pools of esterified fatty acids that can be liberated cial gut metabolites affecting the balance of effector and and further metabolised to meet the energy and other regulatory T cells and orchestrating the immune response biosynthetic needs of different cell types. in the gut. In this review, we are discussing the involvement of fat- Long chain fatty acids (14-22 C), such as the saturated ty acids in immunity, particularly in T cells, and cancer, with palmitic acid (C16:0) and monounsaturated oleic acid focus on their roles as energy substrates, regulators of cell (C18:1), can also be sensed by CD36, a fatty acid trans- survival, proliferation and effector function. Increasing locase required for the uptake of fatty acids in the gut [19], evidence supports the notion that fatty acids can influence liver [20], myocardium, skeletal muscle and adipose tissue the biological behaviour of immune and other cell types [21, 22]. CD36 expression in endothelial cells (EC) is in- when involved in pathophysiological conditions, such as strumental for the optimal translocation of long chain fatty metabolic disorders, autoimmune diseases and cancer; acids from circulation to cardiomyocytes, skeletal muscle therefore, exploring the metabolism and properties of fatty and adipose tissue, with

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