33 2 Macrophage Metabolic Reprogramming in Diabetes points, after citrate, and after succinate, resulting in the accumulation of these two metabolites. The TCA cycle in macrophages has been elegantly reviewed in detail by Ryan and O’Neill (51). A short summary of the most important consequences of metabolic reprogramming is given below. The first consequence of metabolic reprogramming is a breakpoint of the TCA cycle after citrate, due to lower expression of isocitrate dehydrogenase (Figure 3B). This enzyme is responsible for the conversion of isocitrate to α-ketoglutarate and when expressed at lower levels results in more citrate in cells. The accumulated citrate can be transported into the cytosol by mitochondrial citrate carrier family 25 member 1 (SLC25a1) in exchange for malate (52). This carrier is highly expressed in macrophages stimulated by inflammatory signals leading to citrate accumulation in the cytosol (53). Once in the cytosol, citrate can be converted by ATP citrate lyase into acetyl-CoA and oxaloacetate and used for the synthesis of fatty acids, cell membranes and prostaglandins (54), or it can be transported into the nucleus and converted into acetyl-CoA by citrate lyase (55). As the enzyme ATP citrate lyase is upregulated in classically activated macrophages (56) this could lead to higher levels of cellular acetyl-CoA. Acetyl-CoA can then be used for lysine acetylation of proteins, such as histones, by acetyltransferases, therefore having an impact on gene expression (as explained in later paragraphs), or for de novo lipogenesis. The second consequence of metabolic reprogramming is a breakpoint after succinate due to the inhibition of succinate dehydrogenase by competitive inhibitor itaconate, which will result in succinate accumulation (Figure 3C). Itaconate is produced by cis-aconitate decarboxylase, also called immune-responsive gene 1, and is present in higher quantities in classically activated macrophages, in which it also induces lactate dehydrogenase, contributing to the buildup of lactate (57). In addition, the above-mentioned accumulation of citrate can contribute to succinate accumulation because citrate can be converted to cis-aconitate in mitochondria and can then be further converted to itaconate by cis-aconitate decarboxylase. The levels of succinate are also increasing as a consequence of increasing levels of glutamine anaplerosis. This means that glutamine is converted via α-ketoglutarate into succinate through glutaminolysis or through an upregulated γ-aminobutyric acid (GABA) shunt. This shunt is a TCA cycle bypass which uses glutamine as a substrate to produce succinate, passing through glutamate, GABA, and succinic semialdehyde (58). Incidentally, succinate dehydrogenase is also the second complex of the mitochondrial respiratory chain, which is a series of enzyme complexes that transfer electrons inside the mitochondrial matrix in exchange for protons, that are then pumped out. Succinate dehydrogenase generates ubiquinol from ubiquinone using the electrons obtained from succinate oxidation. Ubiquinol is
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