Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis.

BACKGROUND

Metabolic dysfunction-associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date.

METHODS

We used a network analysis approach to delineate protein-protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl-CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein-protein interaction (PPI) network of the transition from steatosis to MASH in patient samples. ACOT1 overexpression and silencing effects were tested on C57BL/6 mice exposed to high-fat diet (HFD) and inoculated with an adenoviral system to modulate expression. Transcriptomic and untargeted lipidomic profiles were performed on the mouse livers.

RESULTS

ACOT1 expression was 3-fold higher in MASH as compared to steatosis. In patient samples, was significantly correlated with the severity of MASH as reflected by the nonalcoholic fatty liver disease score. Experimental validation showed that downregulation of ACOT1 resulted in decreased lipid accumulation and prevention of MASH . Conversely, upregulation of ACOT1 via an adenoviral vector resulted in development of MASH, whereas control mice only developed steatosis. Lipidomic analysis revealed glycerophospholipids to be especially abundant in MASH accelerated by ACOT1 upregulation.

CONCLUSION

These results suggest that ACOT1 contributes to the transition from steatosis to MASH through modulation of glycerophospholipid accumulation and its potential as a novel therapeutic target in MASH. This trial is registered with NCT02148471.