@article {1574697, title = {Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice}, journal = {Sci Transl Med}, volume = {12}, number = {557}, year = {2020}, month = {2020 Aug 19}, abstract = {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 down-regulated 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.}, issn = {1946-6242}, doi = {10.1126/scitranslmed.aay8798}, author = {Alsamman, Sarah and Christenson, Stephanie A and Yu, Amy and Ayad, Nadia M E and Mooring, Meghan S and Segal, Joe M and Hu, Jimmy Kuang-Hsien and Schaub, Johanna R and Ho, Steve S and Rao, Vikram and Marlow, Megan M and Turner, Scott M and Sedki, Mai and Pantano, Lorena and Ghoshal, Sarani and Ferreira, Diego Dos Santos and Ma, Hsiao-Yen and Duwaerts, Caroline C and Espanol-Suner, Regina and Wei, Lan and Newcomb, Benjamin and Mileva, Izolda and Canals, Daniel and Hannun, Yusuf A and Chung, Raymond T and Mattis, Aras N and Fuchs, Bryan C and Tager, Andrew M and Dean Yimlamai and Weaver, Valerie M and Mullen, Alan C and Sheppard, Dean and Chen, Jennifer Y} }