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Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype.

ABSTRACT: The insulin-like growth-factor 2 (IGF2) mRNA binding protein p62 is highly expressed in hepatocellular carcinoma tissue. Still, its potential role in liver disease is largely unknown. In this study, we investigated pathophysiological implications of p62 overexpression in mice.We generated mice overexpressing p62 under a LAP-promotor. mRNA expression levels and stability were examined by real-time RT-PCR. Allele-specific expression of Igf2 and H19 was assessed after crossing mice with SD7 animals. The Igf2 downstream mediators pAKT and PTEN were determined by Western blot.Hepatic p62 overexpression neither induced inflammatory processes nor liver damage. However, 2.5week old transgenic animals displayed a steatotic phenotype and improved glucose tolerance. p62 overexpression induced the expression of the imprinted genes Igf2 and H19 and their transcriptional regulator Aire (autoimmune regulator). Neither monoallelic expression nor mRNA stability of Igf2 and H19 was affected. Investigating Igf2 downstream signalling pathways showed increased AKT activation and attenuated PTEN expression.The induction of a steatotic phenotype implies that p62 plays a role in hepatic pathophysiology.

SUBMITTER: Tybl E

PROVIDER: S-EPMC3079004 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype.

Tybl Elisabeth E Shi Fu-Dong FD Kessler Sonja M SM Tierling Sascha S Walter Jörn J Bohle Rainer M RM Wieland Stefan S Zhang Jianying J Tan Eng M EM Kiemer Alexandra K AK

Journal of hepatology 20101026 5

<h4>Background & aims</h4>The insulin-like growth-factor 2 (IGF2) mRNA binding protein p62 is highly expressed in hepatocellular carcinoma tissue. Still, its potential role in liver disease is largely unknown. In this study, we investigated pathophysiological implications of p62 overexpression in mice.<h4>Methods</h4>We generated mice overexpressing p62 under a LAP-promotor. mRNA expression levels and stability were examined by real-time RT-PCR. Allele-specific expression of Igf2 and H19 was ass ...[more]

PMID: 21145819

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Project description:The insulin-like growth factor 2 (IGF2) mRNA binding proteins (IMPs/IGF2BPs) IMP1 and 3 are regarded as oncofetal proteins, whereas the hepatic IMP2 expression in adults is controversially discussed. The splice variant IMP2-2/p62 promotes steatohepatitis and hepatocellular carcinoma. Aim of this study was to clarify whether IMP2 is expressed in the adult liver and influences progression toward cirrhosis. IMP2 was expressed at higher levels in embryonic compared to adult tissues as quantified in embryonic, newborn, and adult C57BL/6J mouse livers and suggested by analysis of publicly available human data. In an IMP2-2 transgenic mouse model microarray and qPCR analyses revealed increased expression of liver progenitor cell (LPC) markers Bex1, Prom1, Spp1, and Cdh1 indicating a de-differentiated liver cell phenotype. Induction of these LPC markers was confirmed in human cirrhotic tissue datasets. The LPC marker SPP1 has been described to play a major role in fibrogenesis. Thus, DNA methylation was investigated in order to decipher the regulatory mechanism of Spp1 induction. In IMP2-2 transgenic mouse livers single CpG sites were differentially methylated, as quantified by amplicon sequencing, whereas human HCC samples of a human publicly available dataset showed promoter hypomethylation. In order to study the impact of IMP2 on fibrogenesis in the context of steatohepatitis wild-type or IMP2-2 transgenic mice were fed either a methionine-choline deficient (MCD) or a control diet for 2-12 weeks. MCD-fed IMP2-2 transgenic mice showed a higher incidence of ductular reaction (DR), accompanied by hepatic stellate cell activation, extracellular matrix (ECM) deposition, and induction of the LPC markers Spp1, Cdh1, and Afp suggesting the occurrence of de-differentiated cells in transgenic livers. In human cirrhotic samples IMP2 overexpression correlated with LPC marker and ECM component expression. Progression of liver disease was induced by combined MCD and diethylnitrosamine (DEN) treatment. Combined MCD-DEN treatment resulted in shorter survival of IMP2-2 transgenic compared to wild-type mice. Only IMP2-2 transgenic livers progressed to cirrhosis, which was accompanied by strong DR. In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells toward steatohepatitis-associated cirrhosis development with poor survival.

Project description:BACKGROUND:Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of the articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the epidermal growth factor receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of the articular cartilage, and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in the cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study. METHODS:Utilizing knee joints from cartilage-specific Mig-6-overexpressing (Mig-6over/over) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining, and semi-quantitative histopathological scoring (OARSI) at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density. RESULTS:Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in the articular cartilage, although Mig-6over/over mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6over/over mice was decreased relative to controls. Immunostaining for MMP13 appeared increased in areas of cartilage degeneration in Mig-6over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6over/over mice. CONCLUSION:Overexpression of Mig-6 in the articular cartilage causes no major developmental phenotype; however, these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways are critical for joint homeostasis and might present a promising therapeutic target for OA.

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Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype.

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Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype.

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