Abstract
The first intermediate in the mitochondrial tricarboxylic acid (TCA) cycle is citrate, which is essential and acts as a metabolic regulator for glycolysis, TCA cycle, gluconeogenesis, and fatty acid synthesis. Within the cytosol, citrate is cleaved by ATP citrate lyase (ACLY) into oxaloacetate (OAA) and acetyl-CoA; OAA can be used for neoglucogenesis or in the TCA cycle, while acetyl-CoA is the precursor of some biosynthetic processes, including the synthesis of fatty acids. Accumulating evidence suggests that citrate is involved in numerous physiological and pathophysiological processes such as inflammation, insulin secretion, neurological disorders, and cancer. Considering the crucial role of citrate to supply the acetyl-CoA pool for fatty acid synthesis and histone acetylation in tumors, in this study we evaluated the effect of citrate added to the growth medium on lipid deposition and histone H4 acetylation in hepatoma cells (HepG2). At low concentration, citrate increased both histone H4 acetylation and lipid deposition; at high concentration, citrate inhibited both, thus suggesting a crucial role of acetyl-CoA availability, which prompted us to investigate the effect of citrate on ACLY. In HepG2 cells, the expression of ACLY is correlated with histone acetylation, which, in turn, depends on citrate concentration. A decrease in H4 acetylation was also observed when citrate was added at a high concentration to immortalized human hepatic cells, whereas ACLY expression was unaffected, indicating a lack of control by histone acetylation. Considering the strong demand for acetyl-CoA but not for OAA in tumor cells, the exogenous citrate would behave like a trojan horse that carries OAA inside the cells and reduces ACLY expression and cellular metabolism. In addition, this study confirmed the already reported dual role of citrate both as a promoter of cell proliferation (at lower concentrations) and as an anticancer agent (at higher concentrations), providing useful tips on the use of citrate for the treatment of tumors.
Highlights
Metabolism is a fundamental biological process in all living organisms for various cellular activities, such as maintaining homeostasis and producing functional energy, building blocks, enzymatic cofactors, and signaling molecules
The HepG2 and immortalized human hepatocyte (IHH) cells were seeded on culture plates and treated for 24 h with sodium citrate and Trichostatin A (TSA), which is an inhibitor of histone deacetylase (HDAC) that prevents the removal of acetyl groups from lysine residues on histone tails
We investigated the effects of different concentrations of extracellularly administered citrate, focusing on its main intracellular functions, i.e., to provide acetyl-CoA for the biosynthesis of fatty acids and histone acetylation
Summary
Metabolism is a fundamental biological process in all living organisms for various cellular activities, such as maintaining homeostasis and producing functional energy, building blocks, enzymatic cofactors, and signaling molecules. These metabolic processes are associated with the generation of several metabolites and in the activation of many enzymes, which are involved in the regulation of gene expression, immunoreactions, cellular apoptosis, and cancer progression. It is widely accepted that cancer cells alter their metabolic pathways to generate more fatty acids from lipogenesis to meet the increasing energy demand for rapid cell division and propagation (De Berardinis and Chandel, 2016). Reprogramming of glucose metabolism and targeting altered metabolic pathways related with glucose metabolism may contribute to designing novel treatment strategies for improving the efficacy of cancer therapy (Luengo et al, 2017; Lin et al, 2020)
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