DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity

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• 作者：Lanfeng Xie¹ ; ² ; ^&dagger ; ; Pi-Xiao Wang² ; ³ ; ^&dagger ; ; Peng Zhang² ; ³ ; ^&dagger ; ; Xiao-Jing Zhang² ; Guang-Nian Zhao² ; ³ ; Aibing Wang⁴ ; Junhong Guo² ; ³ ; Xueyong Zhu² ; ³ ; Qin Zhang¹ ; ^{Zhangq1030@163.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：NAFLD ; non-alcoholic fatty liver disease ; DKK3 ; dickkopf-3 ; HFD ; high fat diet ; ASK1 ; apoptosis signal-regulating kinase 1 ; JNK ; c-Jun N-terminal kinases ; MAPK ; mitogen-activated protein kinase ; NC ; normal chow ; FBG ; fasting blood glucose ; FINS ; fasting serum insulin ; GTTs ; glucose tolerance test ; ITTs ; insulin tolerance tests ; TAG ; triacylglyceride ; TC ; total cholesterol ; NEFA ; non-esterified fatty acid ; H&E ; haematoxylin and eosin ; ALT ; alanine amino transferase ; AST ; aspartate amino transfera
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：65
• 期：1
• 页码：113-124
• 全文大小：3054 K

文摘

Dickkopf-3 (DKK3), a protein belonging to the DKK family, has been extensively investigated in the context of cancer, including liver cancer. However, the role of DKK3 in hepatic steatosis and related metabolic disorders remains largely unexplored.

Methods

We detected the expression of DKK3 in the fatty livers of NAFLD patients and of obese mice and investigated the function of DKK3 in hepatic steatosis and related metabolic disorders by using hepatocyte-specific DKK3 deficiency or overexpression obese mice induced by high fat diet (HFD) or genetic defect (ob/ob). The molecular mechanisms underlying DKK3-regulated hepatic steatosis were further explored and verified in mice.

Results

DKK3 expression was significantly decreased in the livers of NAFLD patients and of obese mice as well as in cultured hepatocytes stimulated with palmitate. Further investigation indicated that specific overexpression of DKK3 in hepatocytes enhanced insulin sensitivity and glucose tolerance, reduced the inflammatory response, and ameliorated the imbalance of lipid metabolism in response to HFD or genetic defects. In contrast, DKK3 deficiency in hepatocytes led to an almost complete reversal of these pathologies. Mechanistically, DKK3 combined with Apoptosis signal-regulating kinase 1 (ASK1) under palmitate stimulation, and thus inhibited the activation of the downstream P38/JNK pathway. Importantly, dominant-negative ASK1 blocked the accelerated effects of DKK3 deficiency, while the constitutively active form of ASK1 overcame the inhibitory effects of DKK3 overexpression on HFD-induced metabolic disorders in vivo.

Conclusion

DKK3 functions as a negative regulator of insulin resistance, hepatic steatosis, and associated inflammatory responses, which depends on its inhibitory regulation of ASK1 activity.

Lay summary

DKK3 expression is decreased in the non-alcoholic fatty liver of humans and mice. Adding DKK3 expression alleviates fatty liver in mice by inhibiting ASK1 activity.