The unusual effect of exogenous citrate on HepG2 cells

Citrate, the first product of the Krebs cycle, is an essential intermediate located at the crossroads of metabolic pathways and a crucial sensor of ATP level by inhibition of strategic glycolytic enzymes through negative feedback. In mitochondria, citrate may either be oxidized via the Krebs cycle or exported outside of mitochondria. Cytosolic citrate is processed by ATP citrate lyase to produce cytosolic acetyl CoA, which sustains the cell proliferation by lipid synthesis or histone acetylation. The role of citrate and ATP citrate lyase might be particularly important in reprogramming of cancer cell metabolism. Cancer cells exhibit reprogrammed pathways of nutrient acquisition and metabolism in order to support the bioenergetic, biosynthetic, and redox demands. The metabolic phenotype of cancer cells is aerobic glycolysis (or Warburg effect) characterized by increased uptake of glucose and increased rate of glycolysis to lactate in the presence of oxygen. With this aim we have treated HepG2 cells, maintained in medium with high and low concentration of glucose, with different concentration of sodium citrate. The results show the effects of citrate on viability, ROS and lipid levels, and the mitochondrial membrane potential. Furthermore, the results show that the expression of ATP citrate lyase is correlated at the histone acetylation.