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

Sarah Alsamman; Stephanie A Christenson; Amy Yu; Nadia M E Ayad; Meghan S Mooring; Joe M Segal; Jimmy Kuang-Hsien Hu; Johanna R Schaub; Steve S Ho; Vikram Rao; Megan M Marlow; Scott M Turner; Mai Sedki; Lorena Pantano; Sarani Ghoshal; Diego Dos Santos Ferreira; Hsiao-Yen Ma; Caroline C Duwaerts; Regina Espanol-Suner; Lan Wei; Benjamin Newcomb; Izolda Mileva; Daniel Canals; Yusuf A Hannun; Raymond T Chung; Aras N Mattis; Bryan C Fuchs; Andrew M Tager; Dean Yimlamai; Valerie M Weaver; Alan C Mullen; Dean Sheppard; Jennifer Y Chen

doi:10.1126/scitranslmed.aay8798

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

Sci Transl Med. 2020 Aug 19;12(557):eaay8798. doi: 10.1126/scitranslmed.aay8798.

Authors

Sarah Alsamman¹, Stephanie A Christenson², Amy Yu¹, Nadia M E Ayad^{3

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 Duwaerts^{1

13}, Regina Espanol-Suner¹⁴, Lan Wei¹⁰, Benjamin Newcomb¹⁵, Izolda Mileva¹⁵, Daniel Canals¹⁵, Yusuf A Hannun¹⁵, Raymond T Chung¹⁶, Aras N Mattis^{13

17}, Bryan C Fuchs¹⁰, Andrew M Tager¹⁸, Dean Yimlamai⁵, Valerie M Weaver^{3

4

14

19

20

21}, Alan C Mullen¹⁶, Dean Sheppard^{22

12}, Jennifer Y Chen^{23

13}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acid Ceramidase*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Fibrosis
Hepatic Stellate Cells* / metabolism
Humans
Mice
Signal Transduction

Substances

Adaptor Proteins, Signal Transducing
Acid Ceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding