The role of PEPCK-C in cataplerosis in the liver. The reactions of the citric acid cycle are presented, with the major end-products shown in gold boxes; the large red box represents the mitochondrial membrane. The concentrations of amino acids, β-hydroxybutyrate, glucose and triglyceride were determined from blood samples, while the levels of malate and pyruvate were determined from freeze-clamped liver. The ablation of PEPCK-C (shown by a red bar) results in a 10-fold increase in the concentration of malate in the liver (we did not distinguish between malate in the cytosol and the mitochondria) and a build-up of cycle intermediates . This leads to a decrease in the rate of citric acid cycle flux and the resultant accumulation of acetyl CoA, which is subsequently converted to ketone bodies and released by the liver. The rate of fatty acid oxidation in the PEPCK-C-/- mice is also markedly decreased, resulting in an increase in triglyceride synthesis from these fatty acids that leads to the development of a fatty liver. There is also a marked increase in the concentration of amino acids in the blood that were generated from citric acid cycle intermediates. The increased rate of flux of intermediates leaving the citric acid cycle is denoted by heavy arrows.