Science translational medicine · 2020
Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Alsamman Sarah, Christenson Stephanie A, Yu Amy, Ayad Nadia M E, Mooring Meghan S, Segal Joe M, Hu Jimmy Kuang-Hsien, Schaub Johanna R, Ho Steve S, Rao Vikram, Marlow Megan M, Turner Scott M, Sedki Mai, Pantano Lorena, Ghoshal Sarani, Ferreira Diego Dos Santos, Ma Hsiao-Yen, Duwaerts Caroline C, Espanol-Suner Regina, Wei Lan, Newcomb Benjamin, Mileva Izolda, Canals Daniel, Hannun Yusuf A, Chung Raymond T, Mattis Aras N, Fuchs Bryan C, Tager Andrew M, Yimlamai Dean, Weaver Valerie M, Mullen Alan C, Sheppard Dean, Chen Jennifer Y
Аннотация
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.