The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis.

Abstract

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: Yan-Xiao Ji, Zan Huang, Xia Yang, Xiaozhan Wang, Ling-Ping Zhao, Pi-Xiao Wang, Xiao-Jing Zhang, Michele Alves-Bezerra, Lin Cai, Peng Zhang, Yue-Xin Lu, Lan Bai, Mao-Mao Gao, Huan Zhao, Song Tian, Yong Wang, Zhi-Xiang Huang, Xue-Yong Zhu, Yan Zhang, Jun Gong, Zhi-Gang She, Feng Li, David E Cohen, Hongliang Li
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 2 Pg. 213-223 (02 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29291351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Neoplasm Proteins
• Nuclear Proteins
• TRIM47 protein, human
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• MAP Kinase Kinase 4
• CYLD protein, mouse
• Deubiquitinating Enzyme CYLD
• Cysteine Endopeptidases

Topics

• Animals
• Carrier Proteins (genetics)
• Cysteine Endopeptidases (chemistry, genetics, metabolism)
• Deubiquitinating Enzyme CYLD
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Haplorhini
• Humans
• Inflammation (genetics, physiopathology)
• Liver (metabolism, pathology)
• MAP Kinase Kinase 4 (genetics)
• MAP Kinase Kinase Kinases (chemistry, genetics, metabolism)
• Metabolic Syndrome (genetics, pathology)
• Mice
• Neoplasm Proteins (genetics)
• Non-alcoholic Fatty Liver Disease (genetics, physiopathology)
• Nuclear Proteins (genetics)
• Protein Binding (genetics)
• Severity of Illness Index
• Signal Transduction (genetics)
• p38 Mitogen-Activated Protein Kinases (genetics)