دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.
المؤلفون: Alsamman S; Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA., Christenson SA; Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Yu A; Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA., Ayad NME; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.; UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA., Mooring MS; Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA., Segal JM; Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA., Hu JK; Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA., Schaub JR; Pliant Therapeutics, South San Francisco, CA 94080, USA., Ho SS; Pliant Therapeutics, South San Francisco, CA 94080, USA., Rao V; Pliant Therapeutics, South San Francisco, CA 94080, USA., Marlow MM; Pliant Therapeutics, South San Francisco, CA 94080, USA., Turner SM; Pliant Therapeutics, South San Francisco, CA 94080, USA., Sedki M; Internal Medicine, Kaiser Permanente, San Francisco, CA 94115, USA., Pantano L; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA., Ghoshal S; Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA., Ferreira DDS; 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., Ma HY; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Duwaerts CC; Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.; Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA., Espanol-Suner R; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA., Wei L; Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA., Newcomb B; Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA., Mileva I; Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA., Canals D; Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA., Hannun YA; Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA., Chung RT; Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Mattis AN; Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA., Fuchs BC; Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA., Tager AM; Division of Pulmonary and Critical Care Medicine, Fibrosis Research Center, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA., Yimlamai D; Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA., Weaver VM; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.; UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA.; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA., Mullen AC; Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Sheppard D; 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.; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Chen JY; Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA. dean.sheppard@ucsf.edu jennifer.chen4@ucsf.edu.; Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
المصدر: Science translational medicine [Sci Transl Med] 2020 Aug 19; Vol. 12 (557).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science
مواضيع طبية MeSH: Acid Ceramidase* , Hepatic Stellate Cells*/metabolism, Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Fibrosis ; Humans ; Mice ; Signal Transduction
مستخلص: 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.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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معلومات مُعتمدة: P30 DK026743 United States DK NIDDK NIH HHS; K23 HL123778 United States HL NHLBI NIH HHS; K08 DK114548 United States DK NIDDK NIH HHS; P01 CA097132 United States CA NCI NIH HHS; R35 CA242447 United States CA NCI NIH HHS; R35 GM118128 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Adaptor Proteins, Signal Transducing)
EC 3.5.1.23 (Acid Ceramidase)
تواريخ الأحداث: Date Created: 20200821 Date Completed: 20210623 Latest Revision: 20220716
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7976849
DOI: 10.1126/scitranslmed.aay8798
PMID: 32817366
قاعدة البيانات: MEDLINE
الوصف
تدمد:1946-6242
DOI:10.1126/scitranslmed.aay8798