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

被引：78

作者：

Alsamman, Sarah ^{[1
]}

Christenson, Stephanie A. ^{[2
]}

Yu, Amy ^{[1
]}

Ayad, Nadia M. E. ^{[3
,4
]}

Mooring, Meghan S. ^{[5
]}

Segal, Joe M. ^{[1
]}

Hu, Jimmy Kuang-Hsien ^{[6
]}

Schaub, Johanna R. ^{[7
]}

Ho, Steve S. ^{[7
]}

Rao, Vikram ^{[7
]}

Marlow, Megan M. ^{[7
]}

Turner, Scott M. ^{[7
]}

Sedki, Mai ^{[8
]}

Pantano, Lorena ^{[9
]}

Ghoshal, Sarani ^{[10
]}

Ferreira, Diego Dos Santos ^{[11
,12
]}

Ma, Hsiao-Yen ^{[13
]}

Duwaerts, Caroline C. ^{[1
,14
]}

Espanol-Suner, Regina ^{[15
]}

Wei, Lan ^{[10
]}

Newcomb, Benjamin ^{[16
,17
,18
]}

Mileva, Izolda ^{[16
,17
,18
]}

Canals, Daniel ^{[16
,17
,18
]}

Hannun, Yusuf A. ^{[16
,17
,18
]}

Chung, Raymond T. ^{[19
]}

Mattis, Aras N. ^{[14
,20
]}

Fuchs, Bryan C. ^{[10
]}

Tager, Andrew M. ^{[21
,22
]}

Yimlamai, Dean ^{[5
]}

Weaver, Valerie M. ^{[3
,4
,15
,23
,24
,25
]}

Mullen, Alan C. ^{[19
]}

Sheppard, Dean ^{[2
,13
]}

Chen, Jennifer Y. ^{[1
,14
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA

[2] Univ Calif San Francisco, Dept Med, Div Pulm Crit Care Allergy & Sleep, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat, San Francisco, CA 94143 USA

[4] UCSF Grad Program Bioengn, UC Berkeley, San Francisco, CA 94143 USA

[5] Yale Univ, Sch Med, Div Pediat Gastroenterol & Hepatol, 333 Cedar St, New Haven, CT 06520 USA

[6] Univ Calif Los Angeles, Sch Dent, Div Oral Biol & Med, Los Angeles, CA 90095 USA

[7] Pliant Therapeut, San Francisco, CA 94080 USA

[8] Kaiser Permanente, Internal Med, San Francisco, CA 94115 USA

[9] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[10] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Div Surg Oncol, Boston, MA 02114 USA

[11] Massachusetts Gen Hosp, Dept Radiol, Inst Innovat Imaging, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA

[12] Harvard Med Sch, Charlestown, MA 02129 USA

[13] Univ Calif San Francisco, Dept Med, Lung Biol Ctr, San Francisco, CA 94158 USA

[14] Univ Calif San Francisco, Dept Med, Liver Ctr, San Francisco, CA 94143 USA

[15] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA

[16] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA

[17] SUNY Stony Brook, Dept Biochem, Stony Brook, NY 11794 USA

[18] SUNY Stony Brook, Stony Brook Canc Ctr, Stony Brook, NY 11794 USA

[19] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Liver Ctr, Boston, MA 02114 USA

[20] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[21] Massachusetts Gen Hosp, Fibrosis Res Ctr, Div Pulm & Crit Care Med, Boston, MA 02114 USA

[22] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA

[23] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[24] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA

[25] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 557期

关键词：

HEPATIC STELLATE CELLS; PRECISION-CUT LIVER; GROWTH-FACTOR-BETA; HIPPO PATHWAY; SPHINGOSINE; 1-PHOSPHATE; FIBROBLAST ACTIVATION; TUMOR-GROWTH; ORGAN SIZE; YAP; TAZ;

D O I：

10.1126/scitranslmed.aay8798

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta-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.

引用

页数：14

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