Overexpression of Insulin-like growth factor II mRNA-binding protein II leads to steatosis in transgenic zebrafish
Date Issued
2007
Date
2007
Author(s)
Lin, Ming-Yuan
Abstract
IGF2 mRNA binding protein 2 (IMP2) was first identified as an auto-antigen p62, which was aberrantly expressed in the human hepatocellular carcinoma (HCC). The roles of IMP2 in HCC development, from chronic liver disease such as fatty liver, cirrhosis to HCC, are still poor understood. Up to now, no any animal model of IMP2 have been reported. In this study, I first intended to establish IMP2 transgenic zebrafish lines by Tol2 transposon-mdiated transgenesis to study the molecular mechanism of IMP2 during the progression of HCC. Full length IMP2 cDNAs were isolated from zebrafish by RT-PCR and RACE. Expression of endogenous IMP2 is rare in the normal liver of adult zebrafish. Transgenic zebrafish lines with different levels of IMP2 over-expression driven by Xenopus EF1a promoter were established. Severe fatty liver (steatosis) was observed in the liver of 2.5 month F1 transgenic zebrafish with high level IMP2 over-expression by HE staining. High accumulating lipid in the cytoplasm pushed the nucleus to the peripheral of the hepatocytes. Zebrafish IGF2a and IGF2b are differentially regulated by IMP2 in the liver of IMP-transgenic zebrafish. Zebrafish IGF2a expressed was activated in the liver of highly IMP2-overexpressed transgenic fish, whereas IGF2b was repressed by IMP2 in dose dependent manner. Expression of zebrafish Akt2 was increased in highly IMP2-overexpressed transgenic zebrafish. By using zebrafish microarray and Q-PCR analysis, enzymes involved in fatty acid synthesis such as acetyl CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase-1, ELOVL1 and cholesterol synthesis ex. 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase were up-regulated in the liver of IMP2-overexpressed transgenic zebrafish. It may result from the increase of key lipogenic transcription factor SREBP1 expression. In addition to SREBP1, transcription factors PPARr and C/EBPa involved in lipogenesis were also up-regulated in the liver of highly IMP2-overexpressed transgenic zebrafish. Due to severe steatosis, ER stress response genes such as XBP1, a key transcriptional regulator of unfolded protein response (UPR); ER chaperones Hspa5/Grp78, Hyou1 and transcription factor ATF4 were strongly activated in the liver of high level IMP2 overexpressed transgenic zebrafish. These data suggest that IMP2 may play a role in fatty liver formation. Overexpression of IMP2 in liver of transgenic zebrafish leads to hepatic steatosis via activation of Akt2
Subjects
zebrafish
fatty liver
steatosis
IMP2
HCC
IGF2BP2
SDGs
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