期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10592
关键词
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资金
- National Science Fund for Distinguished Young Scholars [81425005]
- Key Project of the National Natural Science Foundation [81330005]
- National Natural Science Foundation of China [81170086, 81270184]
- National Science and Technology Support Project [2011BAI15B02, 2012BAI39B05, 2013YQ030923-05, 2014BAI02B01, 2015BAI08B01]
- National Basic Research Program China [2011CB503902]
- Natural Science Foundation of Hubei Province [2013CFB259]
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-beta-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent autophosphorylation, thereby enhancing the activation of downstream IKK beta-NF-kappa B and MKK-JNK-IRS1(307) signalling cascades, while disrupting AKT-GSK3 beta/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.
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