ATP Citrate Lyase

ATP-citrate lyase (ACL) is a cytosolic enzyme upstream of HMG-CoA reductase in the lipid biosynthesis pathway that catalyses the cleavage of mitochondrial-derived citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo cholesterol and fatty acid synthesis. Although ACL is not rate limiting, its strategic position at the intersection of lipid and carbohydrate metabolism, and its potential to regulate lipoprotein metabolism, attracted early interest as a drug target to treat dyslipidemia. ATP-citrate lyase (ACL) is an extramitochondrial enzyme that is expressed in lipogenic tissues such as liver and adipose. Since ACL is the primary enzyme responsible for the production of cytosolic acetyl-CoA, a precursor required for de novo biosyntheses of cholesterol and fatty acids, inhibition of ACL has the potential to reduce cholesterol and triglyceride levels and possibly exert an impact on obesity via reduction of lipogenic factors. ACL is an important enzyme with significant effects on fatty acid and cholesterol metabolism. It is a cytosolic enzyme highly expressed in lipogenic tissues such as the liver and white adipose tissue and is positioned upstream from HMG-CoA reductase in the mammalian cholesterol biosynthesis pathway. It links energy metabolism from carbohydrates to the production of fatty acids through catalyzing acetyl CoA synthesis, the fundamental substrate for the biosynthesis of both fatty acids and cholesterol.