Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes

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• 作者：Yeyou Liang^a ; ¹ ; ^{13416492503@163.com" class="auth_mail" title="E-mail the corresponding author} ; Weiwei Yuan^b ; ¹ ; ^{weiweiyuan@163.com" class="auth_mail" title="E-mail the corresponding author} ; Wensi Zhu^a ; ¹ ; ^{zjgylyy2323@163.com" class="auth_mail" title="E-mail the corresponding author} ; Jiening Zhu^b ; ^{zhujiening0323@163.com" class="auth_mail" title="E-mail the corresponding author} ; Qiuxiong Lin^b ; ^{linqx@aliyu.com" class="auth_mail" title="E-mail the corresponding author} ; Xiao Zou^b ; ^{913175382@qq.com" class="auth_mail" title="E-mail the corresponding author} ; Chunyu Deng^b ; ^{chunyudeng@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yongheng Fu^b ; ^{macklefu@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xilong Zheng^c ; ^{xlzheng@ucalgary.ca" class="auth_mail" title="E-mail the corresponding author} ; Min Yang^b ; ^{mnmyang@aliyun.com" class="auth_mail" title="E-mail the corresponding author} ; Shulin Wu^b ; ^{doctorwushulin@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xiyong Yu^b ; ^{yuxycn@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Zhixin Shan^b ; ^{zhixinshan@aliyun.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MIF ; macrophage migration inhibitory factor ; GLUT4 ; facilitated glucose transporter ; member 4 ; DCM ; diabetic cardiomyopathy ; RNAi ; RNA interference ; EMSA ; electrophoretic mobility shift assay ; NMVCs ; neonatal mouse ventricular cardiomyocytes ; T1D ; type 1 diabetes ; T2D ; type 2 diabetes ; HFD ; high-fat diet ; IGTT ; intraperitoneal glucose tolerance test ; BG ; blood glucose ; AUC ; area-under-the-curve ; IPITT ; intraperitoneal insulin tolerance test ; LV ; left ventricular ; FIHC ; fluorescence immunohistoch
• 刊名：Metabolism
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：64
• 期：12
• 页码：1682-1693
• 全文大小：1510 K

文摘

Evidence shows that both macrophage migration inhibitory factor (MIF) and GLUT4 glucose transporter are involved in diabetic cardiomyopathy (DCM), but it remains largely unknown whether and how MIF regulates GLUT4 expression in cardiomyocytes. The present study aims to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes.

Material and methods

Activations of AKT and AMPK signaling, and expressions of MIF, GLUT4 and the candidate GLUT4 regulation associated transcription factors in the diabetic mouse myocardium were determined. The screened transcription factors mediating MIF-promoted GLUT4 expression were verified by RNA interference (RNAi) and electrophoretic mobility shift assay (EMSA), respectively.

Results

MIF was increased, but GLUT4 was decreased in the diabetic mouse myocardium. MIF could enhance glucose uptake and up-regulate GLUT4 expression in NMVCs. Expressions of transcription factor MEF2A, -2C, -2D and Zac1 were significantly up-regulated in MIF-treated neonatal mouse ventricular cardiomyocytes (NMVCs), and markedly reduced in the diabetic myocardium. Knockdown of MEF2A, -2C, -2D and Zac1 could significantly inhibit glucose uptake and GLUT4 expression in cardiomyocytes. Moreover, EMSA results revealed that transcriptional activities of MEF2 and Zac1 were significantly increased in MIF-treated NMVCs. AMPK signaling was activated in MIF-stimulated NMVCs, and AMPK activator AICAR could enhance MEF2A, -2C, -2D, Zac1 and GLUT4 expression. Additionally, MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74, suggesting the involvement of CD74-dependent AMPK activation.

Conclusions

Transcription factor MEF2 and Zac1 mediate MIF-induced GLUT4 expression through CD74-dependent AMPK activation in cardiomyocytes.