Journal
NATURE MEDICINE
Volume 24, Issue 2, Pages 213-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4461
Keywords
-
Funding
- National Science Fund for Distinguished Young Scholars [81425005]
- National Natural Science Foundation [81330005, 81630011, 91639304]
- National Science and Technology Support Project [2014BAI02B01, 2015BAI08B01]
- National Key Research and Development Program [2013YQ030923-05, 2016YFF0101500]
- National Natural Science Foundation of China [81770053, 91729303]
- National Institutes of Health [DK048873, DK056626, DK103046]
Ask authors/readers for more resources
Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available