Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis

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• 作者：Mei Xiang¹ ; ² ; ³ ; ^&dagger ; ; Pi-Xiao Wang² ; ³ ; ^&dagger ; ; Ai-Bing Wang⁵ ; ^&dagger ; ; Xiao-Jing Zhang⁴ ; Yaxing Zhang² ; ³ ; Peng Zhang² ; ³ ; Fang-Hua Mei² ; ³ ; Man-Hua Chen¹ ; ^{chenmh@aliyun.com" class="auth_mail" title="E-mail the corresponding author} ; Hongliang Li² ; ³ ; ^{lihl@whu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TRAF1 ; Tumor necrosis factor receptor-associated factor 1 ; NAFLD ; non-alcoholic fatty liver disease ; HFD ; high fat diet ; KO ; knockout ; LTG ; liver-specific TRAF1 transgenic ; NTG ; non-transgenic ; TNFR ; Tumor necrosis factor receptor ; GTT ; glucose tolerance test ; ITT ; insulin tolerance test ; AUC ; areas under the curve ; TG ; triglyceride ; TC ; total cholesterol ; NEFA ; non-esterified fatty acid ; HOMA-IR ; homeostasis model assessment of the IR index ; ALT ; alanine amino transferase ; AST ; aspartate amino
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1365-1377
• 全文大小：4518 K

文摘

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an important adapter protein that is largely implicated in molecular events regulating immunity/inflammation and cell death. Although inflammation is closely related to and forms a vicious circle with insulin dysfunction and hepatic lipid accumulation, the role of TRAF1 in hepatic steatosis and the related metabolic disorders remains unclear.

Methods

The participation of TRAF1 in the initiation and progression of hepatic steatosis was evaluated in high fat diet (HFD)-induced and genetic obesity. Mice with global TRAF1 knockout or liver-specific TRAF1 overexpression were employed to investigate the role of TRAF1 in insulin resistance, inflammation, and hepatic steatosis based on various phenotypic examinations. Molecular mechanisms underlying TRAF1-regulated hepatic steatosis were further explored in vivo and in vitro.

Results

TRAF1 expression was significantly upregulated in the livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. In response to HFD administration or in ob/ob mice, TRAF1 deficiency was hepatoprotective, whereas the overexpression of TRAF1 in hepatocytes contributed to the pathological development of insulin resistance, inflammatory response and hepatic steatosis. Mechanistically, hepatocyte TRAF1 promotes hepatic steatosis through enhancing the activation of ASK1-mediated P38/JNK cascades, as evidenced by the fact that ASK1 inhibition abolished the exacerbated effect of TRAF1 on insulin dysfunction, inflammation, and hepatic lipid accumulation.

Conclusions

TRAF1 functions as a positive regulator of insulin resistance, inflammation, and hepatic steatosis dependent on the activation of ASK1-P38/JNK axis.