FIGURE 5.

Proposed mechanism of citrate effect at a higher concentration. In the absence of exogenous citrate or with low citrate concentration (right panel), citrate formed in the TCA cycle moves to the cytoplasm through the citrate/malate exchanger and supplies acetyl groups for histone acetylation and lipid biosynthesis. Since citrate is converted by ATP citrate lyase (ACLY) in acetyl-CoA and oxaloacetate, which in turn goes back in the mitochondria after reduction to malate in exchange with citrate, the full process results in an outflow of acetyl groups. When citrate is administered at a high concentration (left panel), the oxaloacetate accumulates in the cytosol because of the lack of reducing equivalents needed to convert to malate, due to citrate itself acting as an inhibitor of glycolysis. The equilibrium balance of the reaction catalyzed by ACLY is shifted toward the reagents, lowering the availability of acetyl groups for lipid biosynthesis and histone acetylation.