Exploring the Role of ATP-Citrate Lyase in the Immune System

Abstract

Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

Keywords: ATP-citrate lyase; acetyl-CoA; histone acetylation; macrophage; metabolism.

Figure 1

The role of acetyl-CoA and ATP-citrate lyase (ACLY) in de novo lipogenesis and epigenetic modifications. Acetyl-CoA (AcCoA) is predominantly produced in mitochondria through oxidation of glycolysis-derived pyruvate by pyruvate dehydrogenase complex (PDC) and through fatty acid oxidation (FAO). AcCoA condensation with oxaloacetate in the tricarboxylic acid cycle (TCA) produces citrate, which can be exported from mitochondria through the mitochondrial citrate carrier, SLC25A1. Citrate is converted by ACLY localized in the cytosol and the nucleus to AcCoA and oxaloacetate. Oxaloacetate is reduced to malate by cytosolic malate dehydrogenase (MDH), providing the source of NAD⁺ to support glycolysis. Malate is imported back into the mitochondria through SLC25A1, completing the citrate-malate shuttle. Cytosolic Acetyl-CoA can be carboxylated to malonyl-CoA by acetyl-CoA carboxylase (ACC). Malonyl-CoA provides a substrate for fatty acid synthase (FAS) for de novo fatty acid synthesis. Acetyl-CoA can also be as a substrate of acetylation of cytosolic and nuclear proteins. These reactions are catalyzed by histone acetyltransferases (HATs) whereas histone deacetylases (HDACs) mediate the removal of acetyl group. Acyl-CoA synthetase short-chain family member 2 (ACSS2) offers an alternative source of cytosolic or nuclear acetyl-CoA by employing acetate imported from extracellular sources or recycling acetate from histone deacetylation reactions. α-KG, α-ketoglutarate.

Figure 2

ACLY in macrophages and T cells. (A) Macrophage pro-inflammatory (M1) activation by toll-like receptor 4 (TLR4) ligand lipopolysaccharide (LPS) or alternative (M2) activation by interleukin (IL)-4 induces Akt-dependent phosphorylation and activation of ACLY. TLR4 activation enhances glycolysis and, in the early phase of inflammatory response, increases TCA cycle flux to citrate. citrate translocates to cytosol and the nucleus for ACLY-dependent acetyl-CoA (AcCoA) formation. In IL-4-stimulated cells, both fatty acid oxidation (FAO) and glycolysis contribute to AcCoA generation. ACLY-dependent AcCoA provides substrate for histone acetylation, which supports increased expression of pro-inflammatory genes (il6, il12b) or IL-4 target genes (Arg1, Retnla, Mgl2). (B) T-cell receptor ligation during activation of effector T cells increases glycolysis, thereby enhancing pyruvate to lactate conversion by lactate dehydrogenase (LDH). This conversion promotes citrate exit from the TCA cycle, driving cytosolic AcCoA generation by ACLY. Under inflammatory conditions, extracellular lactate may enter T cells and feed to TCA cycle, providing a source of citrate. ACLY-derived AcCoA supports de novo lipogenesis in activated T cells, and provides substrate for histone acetylation, which is necessary for increased expression of ifng. De novo lipogenesis promotes il17a expression in activated T_H17 cells.