J Hepatol.2016 Mar 23. pii: S0168-8278(16)30077-0. doi: 10.1016/j.jhep.2016.03.006. [Epub ahead of print]
Tumor necrosis factor receptor-associated factor 5 (Traf5) acts as an essential negative regulator of hepaticsteatosis.
Gao L1,Wang PX2,Zhang Y2,Yu CJ3,Ji Y2,Wang X4,Zhang P2,Jiang X4,Jin H1,Huang Z5,Zhang ZR3,Li H6.
Abstract
BACKGROUND & AIMS:
Obesity-related metabolic inflammation, insulin resistance (IR), and excessive fat accumulationare linked phenomena that promote the progression of non-alcoholic fatty liver disease (NAFLD). Previous research has indicated that CD40-TRAF5 signaling protects against obesity-related metabolic disorders; however, the precise roles and underlying mechanisms of TRAF5 in obesity-induced pathological processes have not been fully elucidated.
METHODS:
TRAF5 expression was evaluated in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in palmitate-treated hepatocytes. Gain- or loss-of-function approaches were used to investigate the specific roles and mechanisms of hepaticTraf5 under obesity-related pathological conditions.
RESULTS:
TRAF5 expression was decreased in the fatty livers of both NAFLD patients and obese mice, and in palmitate-treated hepatocytes in vitro.Traf5 overexpression significantly suppressed nonalcoholic steatohepatitis (NASH)-like phenotypes in mice after HFD treatment for 24 weeks and inhibited the progression of NAFLD in ob/ob mice. Conversely, Traf5 deficiency resulted in the deterioration of metabolic disorders induced by HFD. Investigations of the underlying mechanisms revealed that Traf5 regulates hepatic steatosis by targeting Jnk signaling. Specifically, Jnk1 rather than Jnk2 is responsible for the function of Traf5 in metabolic disorders, as evidenced by the fact that Jnk1 ablation markedly ameliorates the detrimental effects of Traf5 deficiency on obesity, inflammation, IR, hepatic steatosis and fibrosis.
CONCLUSION:
Traf5 negatively regulates NAFLD/NASH and related metabolic dysfunctions by blocking Jnk1 activity, which represents a potential therapeutic target for obesity-related metabolic disorders.
LAY SUMMARY:
Lipid accumulation in the liver induces degradation of Traf5. Increasing Traf5 ameliorates non-alcoholic fatty liver by blocking Jnk1 activity.
Copyright © 2016. Published by Elsevier B.V.
KEYWORDS:
Hepatic steatosis; Insulin resistance; JNK; TRAF5
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