ACLY

ACLY, short for ATP citrate lyase, is a cytosolic enzyme that links carbohydrate metabolism to lipid biosynthesis. It catalyzes the ATP-dependent cleavage of citrate into acetyl-CoA and oxaloacetate, using CoA as a substrate. The produced cytosolic acetyl-CoA serves as the building block for fatty acid and cholesterol synthesis and also provides acetyl groups for protein and histone acetylation.

Localization and substrates: ACLY operates in the cytosol, where it uses citrate exported from mitochondria as its substrate. The citrate supply connects mitochondrial energy and carbon flux with cytosolic lipid production, enabling the synthesis of fatty acids and cholesterol required for membrane formation and signaling.

Genetics and regulation: In humans, the enzyme is encoded by the ACLY gene. Regulation of ACLY involves nutrient signaling and energy status. Insulin and other lipogenic signals promote ACLY activity and expression, while AMP-activated protein kinase (AMPK) can inhibit ACLY through phosphorylation in response to low energy. ACLY activity is often upregulated in conditions requiring de novo lipogenesis, including certain cancers.

Clinical relevance and therapeutic context: Dysregulated ACLY activity is associated with metabolic disorders and cancer cell metabolism, where increased acetyl-CoA supply supports rapid lipid synthesis. Pharmacological inhibition of ACLY, notably by bempedoic acid, reduces hepatic cholesterol synthesis and lowers low-density lipoprotein (LDL) cholesterol, illustrating ACLY as a therapeutic target for metabolic disease and cardiovascular risk management.

See also: lipid metabolism, acetyl-CoA, histone acetylation, fatty acid synthesis.