Pharmacologic inhibition of lipogenesis for the treatment of NAFLD

The hepatic accumulation of excess triglycerides is a seminal event in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). Hepatic steatosis occurs when the hepatic accrual of fatty acids from the plasma and de novo lipogenesis (DNL) is no longer balanced by rates of fatty acid oxidation and secretion of very low-density lipoprotein-triglycerides. Accumulating data indicate that increased rates of DNL are central to the development of hepatic steatosis in NAFLD. Whereas the main drivers in NAFLD are transcriptional, owing to both hyperinsulinemia and hyperglycaemia, the effectors of DNL are a series of wellcharacterised enzymes. Several have proven amenable to pharmacologic inhibition or oligonucleotide-mediated knockdown, with lead compounds showing liver fat-lowering efficacy in phase II clinical trials. In humans with NAFLD, percent reductions in liver fat have closely mirrored percent inhibition of DNL, thereby affirming the critical contributions of DNL to NAFLD pathogenesis. The safety profiles of these compounds have so far been encouraging. It is anticipated that inhibitors of DNL, when administered alone or in combination with other therapeutic agents, will become important agents in the management of human NAFLD. (c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.