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

Autor: Pasini E; University Health Network, Toronto, Canada., Baciu C; University Health Network, Toronto, Canada., Angeli M; University Health Network, Toronto, Canada., Arendt B; University Health Network, Toronto, Canada., Pellegrina D; Ontario Institute for Cancer Research, Toronto, Canada., Reimand J; Ontario Institute for Cancer Research, Toronto, Canada.; University of Toronto, Toronto, Canada., Patel K; University Health Network, Toronto, Canada., Tomlinson G; University Health Network, Toronto, Canada., Mazhab-Jafari MT; University Health Network, Toronto, Canada.; University of Toronto, Toronto, Canada., Kotra LP; University Health Network, Toronto, Canada.; University of Toronto, Toronto, Canada., Fischer S; University Health Network, Toronto, Canada., Allard JP; University Health Network, Toronto, Canada., Humar A; University Health Network, Toronto, Canada., Bhat M; University Health Network, Toronto, Canada.; University of Toronto, Toronto, Canada.
Jazyk: angličtina
Zdroj: International journal of hepatology [Int J Hepatol] 2024 Jul 11; Vol. 2024, pp. 5560676. Date of Electronic Publication: 2024 Jul 11 (Print Publication: 2024).
DOI: 10.1155/2024/5560676
Abstrakt: 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 in vivo on C57BL/6 mice exposed to high-fat diet (HFD) and inoculated with an adenoviral system to modulate ACOT1 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, ACOT1 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 in vivo . 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.
Competing Interests: All authors declare no conflict of interest, financial or otherwise.
(Copyright © 2024 Elisa Pasini et al.)
Databáze: MEDLINE
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