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

by Selleckchem | Nov 15 2023

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.

Comments:

The information you've provided outlines a study or experiment that investigates the potential therapeutic benefits of inhibiting Fatty Acid Synthase (FASN) in the context of non-alcoholic steatohepatitis (NASH), a liver disease characterized by inflammation and fat accumulation in the liver. Here's a breakdown of the key findings from this study:

1. **Rationale**: FASN is targeted because it plays a crucial role in de novo lipogenesis (the creation of new fatty acids), and it is involved in pro-inflammatory and fibrogenic signaling, making it an attractive target for treating NASH.

2. **Experimental Models and Inhibitors**: The study employed both human cell culture and three different diet-induced mouse models of NASH. Three FASN inhibitors were tested: TVB-3664, TVB-3166, and a clinical-stage inhibitor called TVB-2640, also known as denifanstat.

3. **Effects in Human Liver Microtissues**: In human primary liver microtissues, FASN inhibition (FASNi) resulted in a decrease in triglyceride (TG) content, indicating a direct anti-steatotic (anti-fat accumulation) effect.

4. **Effects in Human Hepatic Stellate Cells**: FASNi reduced markers of fibrosis in human hepatic stellate cells, including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). This suggests a potential anti-fibrotic effect.

5. **Effects on Immune Cells**: FASNi reduced the production of Th17 cells in CD4+ T cells exposed to NASH-related cytokines. It also reduced the release of the pro-inflammatory cytokine IL-1β in LPS-stimulated peripheral blood mononuclear cells (PBMCs). This indicates an immunomodulatory effect of FASN inhibition.

6. **Effects in Mouse Models**:
   - In diet-induced NASH mice, FASNi prevented the development of hepatic steatosis (fat accumulation) and fibrosis. It also reduced circulating IL-1β.
   - In mice with established diet-induced NASH, FASNi improved various disease markers, including NAFLD activity score, fibrosis score, ALT (alanine transaminase, a liver enzyme) levels, and TG levels.
   - In the CCl4-induced FAT-NASH mouse model, FASN inhibition reduced hepatic fibrosis, fibrosis markers, and the development of hepatocellular carcinoma (HCC) tumors by 85%. This suggests a potential role for FASN inhibition in preventing liver cancer associated with NASH.

7. **Conclusions**: The results indicate that FASN inhibition has multiple beneficial effects in the context of NASH. It not only reduces fat accumulation in hepatocytes but also attenuates inflammatory and fibrotic processes, involving immune cells and hepatic stellate cells. FASN inhibition, therefore, has the potential to target key hallmarks of NASH, making it a promising therapeutic approach.

These findings suggest that FASN inhibitors like TVB-3664, TVB-3166, and TVB-2640 could be explored as potential treatments for NASH, a condition for which effective therapies are currently limited. However, it's important to note that further research and clinical trials are needed to fully understand the safety and efficacy of these inhibitors in humans.