Figure 1.

Citrate metabolism. Citrate is produced in the Krebs cycle from oxaloacetate and acetyl-CoA by citrate synthase (CS). It can be exported from the mitochondria through citrate carrier (CIC). Cytosolic citrate is broken down by ACLY to oxaloacetate and acetyl-CoA. Acetyl-CoA can be used as a substrate for fatty acid synthesis. High levels of cytosolic citrate can directly inhibit the glycolytic enzymes PFK1 and PFK2. PFK1 is also indirectly inhibited by decreased levels of fructose 2,6-bisphosphate and pyruvate kinase (PK) is indirectly inhibited (broken line) due to reduced levels of its activator, fructose-1,6-bisphosphate. Mitochondrial citrate can inhibit pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH). Citrate-derived malonyl-CoA can block fatty acid oxidation (FAO) by inhibiting carnitine palmitoyltransferase 1 (CPT1). Citrate can activate the gluconeogenic enzyme fructose 1,6-bisphosphatase (FBPase1) and ACC, and so stimulate fatty acid synthesis.