Yan FJ, Zhang XJ, Wang WX, Ji YX, Wang PX, Yang Y, Gong J, Shen LJ, Zhu XY, Huang Z, Li H

Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, has been previously identified to be closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis (NASH) is largely unknown. Here, we report the first evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications ...

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induced by a high fat diet (HFD) or a genetic deficiency (ob/ob). Using gain- and loss-of-function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte-specific TRIM8 overexpression, whereas deletion or downregulation of TRIM8 in hepatocytes led to a completely oppose phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates TAK1, thus promoting its phosphorylation and the activation of downstream JNK/p38 and NF-κB signaling. Importantly, the participation of TRIM8 in human NAFLD and NASH was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of NASH-related metabolic disorder.The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on TAK1. This article is protected by copyright. All rights reserved.

Date: Dec. 16, 2016

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