The diversity and breadth of cancer cell fatty acid metabolism

Abstract

Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.

Keywords: Cellular membrane; De novo synthesis; Fatty acid; Lipid; Lipid droplets; Mitochondria; Oxidation; Peroxisome.

Fig. 1

Fatty acid uptake, synthesis, and metabolism pathways. Overview of the extracellular sources of fatty acids, including chylomicrons, VLDL and LDL lipoproteins, albumin-bound free fatty acids, and macropinocytosis, and the intracellular pathways that contribute to the intracellular fatty acid pool. Intracellular sources of fatty acids include de novo fatty acid synthesis from non-lipid substrates, lipid droplet lipolysis and lipophagy, fatty acyl-CoA, and phospholipid hydrolysis. Fatty acids are converted to fatty acyl-CoAs that are substrates for a range of reactions including elongation and desaturation, glycerolipid, glycerophospholipid and sphingolipid synthesis, protein acylation, and oxidation in peroxisomes and mitochondria. ACOT acyl-CoA thioesterases, ACLY ATP citrate lyase, ACSL long-chain acyl-CoA synthase, ACSS cytoplasmic acetyl-CoA synthetase, CD36 cluster of differentiation 36, CE cholesteryl ester, DGAT diacylglycerol acyltransferase, ELOVL elongation of very long-chain fatty acid enzymes, ETC electron transport chain, FABP fatty acid binding protein, FA-CoA fatty acyl-CoA, FA fatty acid, FADS fatty acid desaturases, FATP fatty acid transport protein, GLUT glucose transporter, LDLr low-density lipoprotein receptor, LPL lipoprotein lipase, LPR1 low-density lipoprotein receptor-related protein 1, MCT monocarboxylate transporter, PC phosphatidylcholine, PE phosphatidylethanolamine, PS phosphatidylserine, SCD stearoyl-CoA desaturase, SL sphingolipid, TG triacylglycerols, VLCFA-CoA very-long chain fatty acyl-CoA, VLDLr very low-density lipoprotein receptor

Fig. 2

Simple and complex lipid synthesis pathways. Fatty acyl-CoAs are used as building blocks for glycerolipids, glycerophospholipids, and ceramides and are attached to glycerol or sphingosine backbones through actions of acyltransferases and ceramide synthases. Likewise, acylceramides are generated from ceramide and fatty acyl-CoA. Fatty acids can be liberated through the actions of phospholipases, lysophospholipases, and ceramidases. CDase ceramidase, CerS ceramide synthase, DG diacylglycerol, DGAT diacylglycerol acyltransferase, DGK diacylglycerol kinase, FA-CoA fatty acyl-CoA, FA fatty acid, GPAT glycerol-3-phosphate acyltransferases, LPAAT lysophosphatidate acyl transferase, LPLAT lysophospholipid acyltransferase, LYPLA lysophospholipase A, MG monoacylglycerol, MGAT monoacylglycerol acyltransferase, PC phosphatidylcholine, PE phosphatidylethanolamine, PI phosphatidylinositol, PLA phospholipid lipase, PS phosphatidylserine, SPT1 serine palmitoyltransferase 1, TG triacylglycerols

Fig. 3

Lipolysis and lipophagy of lipid droplet contained neutral lipids. Neutral lipids including triacylglycerols, cholesterol esters, and acylceramides are broken down through the actions of neutral lipases (lipolysis) or lipophagy to liberate fatty acids. Triacylglycerol lipolysis is catalyzed by a series of reactions by ATGL, HSL, and MAGL. ATGL activity is activated by protein-protein interaction with ABHD5 and suppressed by G0S2 and HILPDA. Fatty acids liberated by lipolysis or lipophagy are activated by ACSL to form fatty acyl-CoAs. Triacylglycerol and acylceramide synthesis are catalyzed by DGAT using fatty acyl-CoA and diacylglycerol or ceramide as substrates. ABHD5 abhydrolase domain containing 5, ACSL long-chain acyl-CoA synthase, ATGL adipose triacylglycerol lipase, DG diacylglycerol, DGAT diacylglycerol acyltransferase, FA-CoA fatty acyl-CoA, FA fatty acid, G0S2 G0/G1 switch gene 2, HILPDA hypoxia-inducible lipid droplet-associated protein, HSL hormone-sensitive lipase, MAGL monoglyceride lipase

Fig. 4

Peroxisomal and mitochondrial fatty acid oxidation. Short- and medium-chain fatty acyl-CoAs freely diffuse into the mitochondria and enter beta oxidation, whereas long-chain fatty acyl-CoAs are transported into the mitochondria via the CPT system. Saturated fatty acyl-CoAs directly enter the beta oxidation pathways, whereas unsaturated fatty acyl-CoAs switch between beta oxidation and the auxiliary pathways which process the double bonds. Beta oxidation shortens fatty acyl-CoAs by two carbons to produce acetyl-CoA which is a substrate for the TCA cycle and ATP generation. Very-long chain fatty acyl-CoAs are transported into peroxisomes via ABCD transporters and undergo oxidation to shorten the fatty acyls and produce acyl-carnitines by carnitine octanoyltransferase which are transported to the mitochondrial, where they are converted to fatty acyl-CoAs by the actions of CPT2. Peroxisomal oxidation also produces acetyl-CoA that can be converted to acetylcarnitine by carnitine acetyltransferase or to acetate by acyl-CoA thioesterases. Mitochondrial fatty acid oxidation is reduced by allosteric inhibition of CPT1 by malonyl-CoA which is produced via ACC2 from acetyl-CoA, which itself generated by acetate by ACSS. ABCD ATP-binding cassette transporters, ACAA2 3-ketoacyl-CoA thiolase, ACAD acyl-CoA dehydrogenase, ACC2 acetyl-CoA carboxylases, ACOT acyl-CoA thioesterases, ACSS2 cytoplasmic acetyl-CoA synthetase, CACT carnitine acylcarnitine translocase, CAT carnitine acetyltransferase, COT carnitine octanoyltransferase, CPT1 carnitine palmitoyltransferase 1, CPT2 carnitine palmitoyltransferase 2, ETC electron transport chain, ECH enoyl-CoA hydratase, ECI Δ3, Δ2-enoyl-CoA isomerase, DECR1 2,4-dienoyl CoA-reductase, HADH hydroxyacyl-CoA dehydrogenase, FA-CoA fatty acyl-CoA, S-FAs saturated fatty acids, Un-FAs unsaturated fatty acids including MUFAs and PUFAs, VLCFA-CoA very-long chain fatty acyl-CoA