Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice
| Autor: | Aras N. Mattis, Valerie M. Weaver, Lan Wei, Steve S. Ho, Yusuf A. Hannun, Lorena Pantano, Meghan S. Mooring, Bryan C. Fuchs, Jennifer Y. Chen, Alan C. Mullen, Regina Español-Suñer, Diego dos Santos Ferreira, Dean Yimlamai, Andrew M. Tager, Daniel Canals, Raymond T. Chung, Joe M. Segal, Vikram R. Rao, Amy Yu, Johanna R. Schaub, Mai Sedki, Caroline C. Duwaerts, Sarani Ghoshal, Hsiao-Yen Ma, Nadia M. E. Ayad, Scott M. Turner, Jimmy Kuang-Hsien Hu, Benjamin Newcomb, Megan M. Marlow, Stephanie A. Christenson, Izolda Mileva, Dean Sheppard, Sarah Alsamman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Ceramide Acid Ceramidase Medical and Health Sciences Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Fibrosis medicine Hepatic Stellate Cells 2.1 Biological and endogenous factors Animals Humans Aetiology Cancer Adaptor Proteins Signal Transducing biology Chemistry Signal Transducing Signal transducing adaptor protein Adaptor Proteins General Medicine Biological Sciences medicine.disease Sphingolipid Ubiquitin ligase 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Hepatic stellate cell Hepatic fibrosis Signal Transduction |
| Zdroj: | Sci Transl Med Science translational medicine, vol 12, iss 557 |
| Popis: | Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid, ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein, β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most downregulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis. |
| Databáze: | OpenAIRE |
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