The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis

Nat Med. 2018 Feb;24(2):213-223. doi: 10.1038/nm.4461.

Yan-Xiao Ji ¹ ² ³ ⁴, Zan Huang ⁵, Xia Yang ² ³ ⁴, Xiaozhan Wang ² ³ ⁴ ⁶, Ling-Ping Zhao ² ³ ⁴, Pi-Xiao Wang ² ³ ⁴ ⁶, Xiao-Jing Zhang ² ⁶, Michele Alves-Bezerra ⁷, Lin Cai ¹ ² ³, Peng Zhang ¹ ² ³ ⁴, Yue-Xin Lu ² ³ ⁴, Lan Bai ² ⁶, Mao-Mao Gao ² ³ ⁴, Huan Zhao ⁵, Song Tian ² ³ ⁴, Yong Wang ², Zhi-Xiang Huang ², Xue-Yong Zhu ² ³ ⁴, Yan Zhang ² ³ ⁴, Jun Gong ² ³ ⁴ ⁵, Zhi-Gang She ² ³ ⁴ ⁶, Feng Li ³, David E Cohen ⁷, Hongliang Li ¹ ² ³ ⁴ ⁶

Affiliations

1 Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
2 Institute of Model Animal of Wuhan University, Wuhan, China.
3 Basic Medical School, Wuhan University, Wuhan, China.
4 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
5 College of Life Sciences, Wuhan University, Wuhan, China.
6 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
7 Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA.

PMID: 29291351 DOI: 10.1038/nm.4461

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.