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-IRS1(307) 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.

中文翻译：

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肝细胞TRAF3通过靶向TAK1依赖性信号传导来促进肝脏脂肪变性和系统性胰岛素抵抗。

非酒精性脂肪肝疾病（NAFLD）的特征是肝脂肪变性，胰岛素抵抗和全身性促炎反应。在这里，我们显示肿瘤坏死因子受体相关因子3（TRAF3）在肝脂肪变性的小鼠和人类肝脏中被上调。高脂饮食（HFD）24周后，肝脏特异性TRAF3基因敲除小鼠的肥胖，胰岛素抵抗，肝脂肪变性和炎症反应明显改善，而在肝细胞中过表达TRAF3的转基因小鼠则加剧了肥胖。在ob / ob小鼠中证实了TRAF3对肝脂肪变性和相关病理的有害作用。我们进一步显示，响应HFD，肝细胞TRAF3与TGF-β激活的激酶1（TAK1）结合，以诱导TAK1泛素化和随后的自磷酸化，从而增强了下游IKKβ-NF-κB和MKK-JNK-IRS1（307）信号级联的激活，同时破坏了AKT-GSK3β/ FOXO1信号。TRAF3-TAK1相互作用和TAK1泛素化对于TRAF3调节的肝脂肪变性是必不可少的。总之，肝细胞TRAF3以TAK1依赖性方式促进HFD诱导或遗传性肝脂肪变性。