ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is characterized by excess delivery of fatty acids to hepatocytes or the overproduction of fatty acids in hepatocytes by the process of de novo lipogenesis. The synthesis of fatty acids from metabolic precursor substrates such as excess carbohydrates, especially fructose, is a necessary metabolic pathway in all cell types to meet the demands for synthesizing cell and organelle membranes and production of molecules with fatty acid components. Because excess production or availability of fatty acids in hepatocytes is linked to the generation of lipotoxic species such as ceramides when disposal routes are impaired or overwhelmed, inhibiting de novo lipogenesis has been identified as a potential way to treat patients with nonalcoholic steatohepatitis (NASH). Key enzymes of the de novo lipogenesis pathway, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) have been targeted individually with small molecule inhibitors or globally with ligands for nuclear receptors such as FXR with new drugs that are now in clinical trials for patients with NASH. Early data from these trials appear promising, and the drugs targeting the de novo lipogenesis pathway are reviewed in this chapter.
