As a primary metabolic organ in the human body, the liver plays a key role in the regulation of lipid metabolism and is sensitive to energy intake. Hepatic steatosis is an early pathological condition of the liver and can lead to steatohepatitis, cirrhosis, liver failure and severe cardiovascular diseases.
Accumulating evidence indicates that hepatic steatosis is a low-grade inflammatory response and commonly occurs in individuals with insulin resistance and obesity. In the liver, 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.
Thus, insulin resistance, inflammatory response and hepatic steatosis are interconnected pathological events that are often observed in obese individuals. Although extensive research has been conducted in this area, the complex interlinked molecular events and related cellular behaviors that occur during the initiation and progression of hepatic steatosis are not fully understood.
The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family consists of seven members (TRAF1–TRAF7) that can function as signalling adaptors in various pathophysiologic processes. Among TRAF members, TRAF3 was first identified as a protein interacting with CD40 cytoplasmic domain and is ubiquitously expressed.
Previous studies indicated that TRAF3-regulated molecular events and cellular responses are largely cell type- and stress-dependent. Considering the close implication of NF-κB/JNK in insulin function and inflammatory response that intimately associated with fatty acid metabolism in hepatocytes, authors hypothesize that TRAF3 might be involved in the pathogenesis of hepatic steatosis.
They generated hepatocyte-specific TRAF3-KO and TRAF3-transgenic mice and subjected to them to a high-fat diet (HFD) to evaluate the effects of TRAF3 on hepatic steatosis and related metabolic disorder. 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. Authors further show that in response to HFD, hepatocyte TRAF3 binds to TGF-β-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent auto-phosphorylation, thereby enhancing the activation of downstream NF-κB and MKK–JNK– 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.
http://www.nature.com/ncomms/2016/160217/ncomms10592/full/ncomms10592.html
Signaling mechanism in non-alcoholic fatty liver disease
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