Fatty acid binding protein-4 (FABP4) is a hypoxia inducible gene that sensitizes mice to liver ischemia/reperfusion injury

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• 作者：Bingfang Hu¹ ; ² ; ^&dagger ; ; Yan Guo² ; ³ ; ^&dagger ; ; Wojciech G. Garbacz² ; Mengxi Jiang² ; Meishu Xu² ; Hai Huang⁴ ; Allan Tsung⁴ ; Timothy R. Billiar⁴ ; Sadeesh K. Ramakrishnan⁵ ; Yatrik M. Shah⁵ ; Karen S.L. Lam⁶ ; Min Huang¹ ; ^{huangmin@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Wen Xie² ; ⁷ ; ^{wex6@pitt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALT ; alanine aminotransferase ; ARNT ; aryl hydrocarbon receptor nuclear translocator ; AST ; aspartate aminotransferase ; ChIP ; chromatin immunoprecipitation ; EMSA ; electrophoretic mobility shift assay ; FABP4 ; fatty acid binding protein 4 ; GdCl3 ; gadolinium chloride ; HIF-1伪 ; hypoxia inducible factor 1伪 ; HRE ; hypoxia responsive element ; I/R ; ischemia/reperfusion ; LPS ; lipopolysaccharide ; NACA ; N-acetylcysteine amide ; VEGF ; vascular endothelial growth factor ; YC-1 ; 3-(5&prime ; -Hydroxymethyl-2&prime ; -f
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：63
• 期：4
• 页码：855-862
• 全文大小：1317 K

文摘

Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition that involves both hypoxia and inflammation.

Methods

To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1伪 (HIF-1伪) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays.

Results

We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1伪 in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1伪.

Conclusions

FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury.