Fatty Acid Synthase: A Target for the Reversal of Liver Steatosis

Zachary   P.   Evans; Justin   D.   Ellett; Kenneth   D.   Chavin

Abstract

Liver steatosis, or fatty liver, is characterized by the excess accumulation of triglycerides and fatty acids within hepatocytes. This accumulation is marked by an imbalance between the import/synthesis and export/degradation of fat in the liver. Liver steatosis is typically a benign condition, but is associated with severe complications following major liver surgery, as well as the progression of the liver to fibrosis, cirrhosis, and hepatocellular carcinoma. The hallmark of treatment has traditionally been the use of behavioral modification leading to long-term phenotypic reversal. However, the rapid reversal of liver steatosis is essential, especially prior to surgeries including hepatic resection or transplantation. The liver is a primary lipogenic tissue, making the enzyme fatty acid synthase (FAS, EC 2.3.1.85) a logical target for the treatment of steatosis. For steatosis of alcoholic or nonalcoholic etiology, fat accumulation is linked to the de novo synthesis of fatty acids through FAS. Recent reports have shown success using FAS inhibitors to reduce the amount of liver steatosis, and to reduce ischemia/reperfusion injury in those livers. Thus, FAS emerges as a key target for the reversal of hepatic steatosis, both for the preconditioning of livers prior to surgery.

Keywords: Fatty acid synthase liver, steatosis, transplantation, fatty liver disease, cerulenin, EGCG