Acetyl-CoA carboxylase (ACC1/ACC2)

Class

Liver-targeted small-molecule ACC inhibitor (clesacostat)

Pathway

De novo lipogenesis — inhibits conversion of acetyl-CoA to malonyl-CoA, reducing hepatic fatty acid synthesis

Acetyl-CoA carboxylase (ACC) exists in two related forms, ACC1 and ACC2, that catalyze the first committed step of fatty acid synthesis: converting acetyl-CoA into malonyl-CoA. ACC1 is most active in tissues that build new fat molecules, including the liver, while ACC2 sits near mitochondria and uses its malonyl-CoA product to restrain fatty acid burning. Together these enzymes govern how much new fat a cell makes versus how much stored fat it oxidizes for energy. In the liver, excessive de novo lipogenesis (fat built from scratch out of sugars and other carbon sources) contributes to the accumulation of triglycerides within hepatocytes, a hallmark of fatty liver disease. A small molecule that inhibits both ACC isoforms and is engineered to concentrate in the liver aims to blunt this synthetic pathway specifically where it drives disease, while limiting exposure in muscle, heart, and adipose tissue where ACC2 activity is also important for normal fat-burning regulation. This approach reflects a broader principle in metabolic drug design: intervening in a fundamental biosynthetic pathway is most useful when it can be confined to the organ where the pathway has become pathologically overactive.