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...
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | International Journal of Hepatology |
| Online Access: | http://dx.doi.org/10.1155/2024/5560676 |
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| author | Elisa Pasini Cristina Baciu Marc Angeli Bianca Arendt Diogo Pellegrina Jüri Reimand Keyur Patel George Tomlinson Mohammad T. Mazhab-Jafari Lakshmi P. Kotra Sandra Fischer Johane P. Allard Atul Humar Mamatha Bhat |
| author_facet | Elisa Pasini Cristina Baciu Marc Angeli Bianca Arendt Diogo Pellegrina Jüri Reimand Keyur Patel George Tomlinson Mohammad T. Mazhab-Jafari Lakshmi P. Kotra Sandra Fischer Johane P. Allard Atul Humar Mamatha Bhat |
| author_sort | Elisa Pasini |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8a1104729a52410289fad8ac59721ef4 |
| institution | Kabale University |
| issn | 2090-3456 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Hepatology |
| spelling | doaj-art-8a1104729a52410289fad8ac59721ef42025-02-03T10:24:54ZengWileyInternational Journal of Hepatology2090-34562024-01-01202410.1155/2024/5560676Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated SteatohepatitisElisa Pasini0Cristina Baciu1Marc Angeli2Bianca Arendt3Diogo Pellegrina4Jüri Reimand5Keyur Patel6George Tomlinson7Mohammad T. Mazhab-Jafari8Lakshmi P. Kotra9Sandra Fischer10Johane P. Allard11Atul Humar12Mamatha Bhat13University Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkOntario Institute for Cancer ResearchOntario Institute for Cancer ResearchUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkUniversity Health NetworkBackground. 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.http://dx.doi.org/10.1155/2024/5560676 |
| spellingShingle | Elisa Pasini Cristina Baciu Marc Angeli Bianca Arendt Diogo Pellegrina Jüri Reimand Keyur Patel George Tomlinson Mohammad T. Mazhab-Jafari Lakshmi P. Kotra Sandra Fischer Johane P. Allard Atul Humar Mamatha Bhat Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis International Journal of Hepatology |
| title | Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis |
| title_full | Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis |
| title_fullStr | Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis |
| title_full_unstemmed | Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis |
| title_short | Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis |
| title_sort | acyl coa thioesterase 1 contributes to transition of steatosis to metabolic associated steatohepatitis |
| url | http://dx.doi.org/10.1155/2024/5560676 |
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