35 2 Macrophage Metabolic Reprogramming in Diabetes Figure 3: Macrophage metabolic reprograming. (A) Alternatively activated macrophages have an induced fatty acid oxidation (FAO) and produce pyruvate from glycolysis and this is converted in acetyl-CoA, which is then used by the tricarboxylic acid (TCA) cycle to give electrons in the form of NADH and FADH2 to the mitochondrial oxidative phosphorylation (OXPHOS) complexes to produce ATP. (B) When macrophages polarize to classically activated macrophages, metabolic reprogramming takes place and lactate is produced instead of pyruvate, and the TCA cycle is broken at two points, after citrate, and after succinate, resulting in the accumulation of these three metabolites. Citrate accumulates due to lower expression of isocitrate dehydrogenase (IDH) and can either be transported to the cytosol through solute carrier family 25 member 1 (SLC25a1), where it can be converted in acetyl-CoA by ATP citrate lyase (ACLY), or to the nucleus where the same conversion can take place. Acetyl-CoA can then be used for lysine acetylation or for lipogenesis. (C) Other changes in classically activated macrophages include succinate dehydrogenase (SDH) inhibition by itaconate, which is produced by upregulated cis-aconitate decarboxylase (CAD), and this results in succinate accumulation. Succinate levels can also increase as a consequence of augmented levels of glutamine anaplerosis, either through an upregulated GABA (γ-aminobutyric acid) shunt or through glutaminolysis. SDH is also part of the mitochondrial respiratory chain and its inhibition will lead to decreased mitochondrial respiration and increased ROS (reactive oxygen species) production. Succinate inhibits prolyl hydroxylase domain (PHD) proteins, resulting in less hydroxylation of hypoxia-inducible factor 1-alpha (HIF-1a), which circumvents its degradation and allows its binding to hypoxia response elements (HRE) on target genes (61). HIF-1α also promotes the switch to glycolysis by inducing glycolytic enzymes like hexokinase 2 (1st reaction of glycolysis), pyruvate kinase M2 (PKM2, 10th reaction), and glucose-6phosphate isomerase (GPI, 2nd reaction). The enzyme product of the latter is used in the oxidative phase of the pentose phosphate pathway (PPP), which is also upregulated in classically activated macrophages. HIF-1α also upregulates the enzymes lactate dehydrogenase and pyruvate dehydrogenase kinase 1 (PDK1) leading to higher lactate production and lower acetyl-CoA synthesis, respectively. Abbreviations: PEP (Phosphoenolpyruvate), PDH (Pyruvate dehydrogenase).
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