FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models

Sci Rep. 2022 Sep 19;12(1):15661. doi: 10.1038/s41598-022-19459-z.

Abstract

Fatty acid synthase (FASN) is an attractive therapeutic target in non-alcoholic steatohepatitis (NASH) because it drives de novo lipogenesis and mediates pro-inflammatory and fibrogenic signaling. We therefore tested pharmacological inhibition of FASN in human cell culture and in three diet induced mouse models of NASH. Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). In human primary liver microtissues, FASN inhibiton (FASNi) decreased triglyceride (TG) content, consistent with direct anti-steatotic activity. In human hepatic stellate cells, FASNi reduced markers of fibrosis including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). In CD4+ T cells exposed to NASH-related cytokines, FASNi decreased production of Th17 cells, and reduced IL-1β release in LPS-stimulated PBMCs. In mice with diet induced NASH l, FASNi prevented development of hepatic steatosis and fibrosis, and reduced circulating IL-1β. In mice with established diet-induced NASH, FASNi reduced NAFLD activity score, fibrosis score, ALT and TG levels. In the CCl4-induced FAT-NASH mouse model, FASN inhibition decreased hepatic fibrosis and fibrosis markers, and development of hepatocellular carcinoma (HCC) tumors by 85%. These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins
  • Animals
  • Carcinoma, Hepatocellular* / complications
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / prevention & control
  • Cytokines
  • Disease Models, Animal
  • Fatty Acid Synthase, Type I
  • Fatty Acid Synthases
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy
  • Lipopolysaccharides
  • Liver Cirrhosis / complications
  • Liver Neoplasms* / complications
  • Liver Neoplasms* / drug therapy
  • Mice
  • Nitriles
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Piperidines
  • Triazoles
  • Triglycerides

Substances

  • Actins
  • Cytokines
  • Lipopolysaccharides
  • Nitriles
  • Piperidines
  • TVB-2640
  • Triazoles
  • Triglycerides
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Fatty Acid Synthases