Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling

Pi-Xiao Wang, Xiao-Jing Zhang, Pengcheng Luo, Xi Jiang, Peng Zhang, Junhong Guo, Guang-Nian Zhao, Xueyong Zhu, Yan Zhang, Sijun Yang and Hongliang Li ()
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Pi-Xiao Wang: Renmin Hospital of Wuhan University
Xiao-Jing Zhang: Renmin Hospital of Wuhan University
Pengcheng Luo: Renmin Hospital of Wuhan University
Xi Jiang: Renmin Hospital of Wuhan University
Peng Zhang: Renmin Hospital of Wuhan University
Junhong Guo: Renmin Hospital of Wuhan University
Guang-Nian Zhao: Renmin Hospital of Wuhan University
Xueyong Zhu: Renmin Hospital of Wuhan University
Yan Zhang: Renmin Hospital of Wuhan University
Sijun Yang: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University
Hongliang Li: Renmin Hospital of Wuhan University

Nature Communications, 2016, vol. 7, issue 1, 1-22

Abstract: Abstract Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response. Here we show that tumour necrosis factor receptor-associated factor 3 (TRAF3) is upregulated in mouse and human livers with hepatic steatosis. After 24 weeks on a high-fat diet (HFD), obesity, insulin resistance, hepatic steatosis and inflammatory responses are significantly ameliorated in liver-specific TRAF3-knockout mice, but exacerbated in transgenic mice overexpressing TRAF3 in hepatocytes. The detrimental effects of TRAF3 on hepatic steatosis and related pathologies are confirmed in ob/ob mice. We further show that in response to HFD, hepatocyte TRAF3 binds to TGF-β-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent autophosphorylation, thereby enhancing the activation of downstream IKKβ–NF-κB and MKK–JNK–IRS1307 signalling cascades, while disrupting AKT–GSK3β/FOXO1 signalling. The TRAF3–TAK1 interaction and TAK1 ubiquitination are indispensable for TRAF3-regulated hepatic steatosis. In conclusion, hepatocyte TRAF3 promotes HFD-induced or genetic hepatic steatosis in a TAK1-dependent manner.

Date: 2016
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DOI: 10.1038/ncomms10592

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