Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease

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• 作者：Yulia A. Nevzorova¹ ; ^{ynevzorova@ukaachen.de" class="auth_mail" title="E-mail the corresponding author} ; Francisco J. Cubero¹ ; ^&dagger ; ; Wei Hu¹ ; ^&dagger ; ; Fengjie Hao¹ ; Ute Haas¹ ; Pierluigi Ramadori¹ ; Nikolaus Gassler² ; Mareike Hoss³ ; Pavel Strnad¹ ; ⁴ ; Henning W. Zimmermann¹ ; Frank Tacke¹ ; Christian Trautwein¹ ; Christian Liedtke¹ ; ^{cliedtke@ukaachen.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：4-HNE ; 4-Hydroxynonenal ; ACOX ; acyl-CoA oxidase ; AKT ; RAC-alpha serine/threonine protein kinase ; alb-myctg ; transgenic mice with overexpression of c-myc in hepatocytes ; ALD ; alcoholic liver disease ; ALT ; alanine aminotransferase ; Asns ; asparagine synthethase ; AST ; aspartate aminotransferase ; ATP ; adenosine triphosphate ; BrdU ; Bromodeoxyuridine ; Cd36 ; cluster of differentiation-36 ; CHOP ; C/EBP homology protein ; CPT1 ; carnitine palmitoyltransferase ; CYP2E1 ; cytochrome P450 2E1 ; DAPI ; 4&prime ; 6-di
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：64
• 期：3
• 页码：628-640
• 全文大小：6434 K

文摘

Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD.

Methods

Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc^tg) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4 weeks to induce ALD.

Results

Hepatic c-myc was strongly upregulated in human patients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc^tg mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1-derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc^tg mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53.

Conclusions

Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients.