Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.,Science Translational Medicine

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Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.
Science Translational Medicine ( IF 15.8 ) Pub Date : 2020-08-19 , DOI: 10.1126/scitranslmed.aay8798
Sarah Alsamman ₁ , Stephanie A Christenson ₂ , Amy Yu ₁ , Nadia M E Ayad _{3,

4} , Meghan S Mooring ₅ , Joe M Segal ₁ , Jimmy Kuang-Hsien Hu ₆ , Johanna R Schaub ₇ , Steve S Ho ₇ , Vikram Rao ₇ , Megan M Marlow ₇ , Scott M Turner ₇ , Mai Sedki ₈ , Lorena Pantano ₉ , Sarani Ghoshal ₁₀ , Diego Dos Santos Ferreira ₁₁ , Hsiao-Yen Ma ₁₂ , Caroline C Duwaerts _{1,

13} , Regina Espanol-Suner ₁₄ , Lan Wei ₁₀ , Benjamin Newcomb ₁₅ , Izolda Mileva ₁₅ , Daniel Canals ₁₅ , Yusuf A Hannun ₁₅ , Raymond T Chung ₁₆ , Aras N Mattis _{13,

17} , Bryan C Fuchs ₁₀ , Andrew M Tager ₁₈ , Dean Yimlamai ₅ , Valerie M Weaver _{3,

4,

14,

19,

20,

21} , Alan C Mullen ₁₆ , Dean Sheppard _{2,

12} , Jennifer Y Chen _{1,

13}

Affiliation

Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.
Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
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.
Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA.
Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Pliant Therapeutics, South San Francisco, CA 94080, USA.
Internal Medicine, Kaiser Permanente, San Francisco, CA 94115, USA.
Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
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.
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
Liver Center, Department of Medicine, University of California, San Francisco, 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.
Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of Pulmonary and Critical Care Medicine, Fibrosis Research Center, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, 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.

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.

中文翻译：

靶向酸性神经酰胺酶抑制 YAP/TAZ 信号传导以减少小鼠的纤维化。

肝星状细胞 (HSC) 驱动肝纤维化。灭活 HSC 的疗法具有作为抗纤维化剂的临床潜力。我们之前将酸性神经酰胺酶 (aCDase) 确定为抗纤维化靶标。我们发现三环类抗抑郁药 (TCA) 通过抑制 aCDase 和增加生物活性神经鞘脂神经酰胺来减少肝纤维化。我们现在证明，靶向 aCDase 通过泛素连接酶衔接蛋白 β-TrCP 增强其磷酸化介导的蛋白酶体降解来抑制 YAP/TAZ 活性。在纤维化小鼠模型中，HSC 中 aCDase 的药物抑制或 aCDase 基因敲除可降低纤维化、基质硬度和 YAP/TAZ 活性。在晚期纤维化患者中，HSC 中的 aCDase 表达增加。始终如一，神经酰胺最下调的基因特征确定了可以从 aCDase 靶向中受益的晚期纤维化患者。这些发现暗示神经酰胺是 YAP/TAZ 信号传导和 HSC 激活的关键调节剂，并强调 aCDase 作为治疗纤维化的治疗靶点。

更新日期：2020-08-20

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