ATP citrate lyase

Class

ATP citrate lyase inhibitor

ATP citrate lyase (ACLY) is a cytosolic enzyme that converts citrate, a product of the tricarboxylic acid cycle, into acetyl-coenzyme A and oxaloacetate. Acetyl-CoA is the essential building block for synthesizing both fatty acids and cholesterol in the liver. Because cholesterol synthesis depends on this supply of acetyl-CoA, inhibiting ACLY reduces the liver's own cholesterol production. This reduction prompts liver cells to increase the number of low-density lipoprotein (LDL) receptors on their surface, which pulls more LDL cholesterol out of the bloodstream. This mechanism is relevant wherever lowering LDL cholesterol is a therapeutic goal, particularly in cardiovascular disease prevention, and offers an approach distinct from statins, which act on an earlier enzyme in the same cholesterol synthesis pathway. Because ACLY-targeting compounds can be designed to require activation by a liver-specific enzyme, they are converted to their active form primarily in hepatic tissue rather than in muscle, which is relevant to the tolerability profile of this drug class. Modulating a central metabolic enzyme of this kind requires balancing effective reduction of lipid synthesis against broader effects on cellular energy metabolism, since acetyl-CoA also feeds other biosynthetic and signaling pathways throughout the body.