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Making a case for aCDase inhibition
Activation of YAP/TAZ mechanosignaling promotes organ fibrosis. Here, Alsamman et al. investigated acid ceramidase (aCDase) inhibition as a way to reduce liver fibrosis. Ceramide promoted YAP/TAZ degradation to inactivate human hepatic stellate cells (HSCs), and liver fibrosis was reduced in mice deficient in aCDase in HSCs. A ceramide analog inhibited aCDase, promoted YAP degradation, and blocked the progression of liver fibrosis in mice and in rodent and human precision liver slice explants. This study demonstrates how aCDase inhibition alters mechanosignaling in fibrosis and identifies a potential therapeutic target.
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.
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