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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response
tumour necrosis factor receptor-associated factor 3 (TRAF3) expression levels were examined in the liver, muscle and fat of wild-type (WT) mice subjected to an high-fat diet (HFD)-induced hepatic steatosis
Immunofluorescence experiments indicated that the increased expression of TRAF3 was primarily localized in the cytoplasm of hepatocytes, the nuclei of which were marked by an antibody specific for HNF4, a factor expressed in hepatocytes[26] (Fig. 1e)
Summary
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response. 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 impaired insulin signalling pathway, which involves the insulin receptor substrate (IRS) proteins and AKT cascade, results in insulin insensitivity and glucose intolerance This impairment in insulin signalling, together with inflammatory response, promotes hepatic lipid synthesis and steatosis, which in turn contribute to chronic hepatic inflammation and insulin resistance[6,7]. The increased NF-kB and JNK activations by TRAF3 were found in hepatocytes on hepatic ischaemia/ reperfusion injury[23] These previous studies collectively indicated that TRAF3-regulated molecular events and cellular responses are largely cell type- and stress-dependent. We identify positive regulatory role of hepatocyte TRAF3 in hepatic steatosis, insulin resistance and inflammatory response
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