Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice

Sarah Alsamman1, Stephanie A Christenson2, Amy Yu1, Nadia M E Ayad3,4, Meghan S Mooring5, Joe M Segal1, Jimmy Kuang-Hsien Hu6, Johanna R Schaub7, Steve S Ho7, Vikram Rao7, Megan M Marlow7, Scott M Turner7, Mai Sedki8, Lorena Pantano9, Sarani Ghoshal10, Diego Dos Santos Ferreira11, Hsiao-Yen Ma12, Caroline C Duwaerts1,13, Regina Espanol-Suner14, Lan Wei10, Benjamin Newcomb15, Izolda Mileva15, Daniel Canals15, Yusuf A Hannun15, Raymond T Chung16, Aras N Mattis13,17, Bryan C Fuchs10, Andrew M Tager18, Dean Yimlamai5, Valerie M Weaver3,4,14,19,20,21, Alan C Mullen16, Dean Sheppard22,12, Jennifer Y Chen23,13

  1. Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.
  2. Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
  3. Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  4. UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA.
  5. Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA.
  6. Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  7. Pliant Therapeutics, South San Francisco, CA 94080, USA.
  8. Internal Medicine, Kaiser Permanente, San Francisco, CA 94115, USA.
  9. Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
  10. Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
  11. Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  12. Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
  13. Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  14. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  15. Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
  16. Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  17. Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  18. Division of Pulmonary and Critical Care Medicine, Fibrosis Research Center, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
  19. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  20. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  21. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  22. Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA. dean.sheppard@ucsf.edu jennifer.chen4@ucsf.edu.
  23. Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA. dean.sheppard@ucsf.edu jennifer.chen4@ucsf.edu.

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.

Presented By Jennifer Chen

Medicine, MetabolismNicholas Liao2020-08 (Aug)