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Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver
Article first published online: 10 MAR 2008
DOI: 10.1111/j.1872-034X.2008.00336.x
© 2008 The Japan Society of Hepatology
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How to Cite
Longato, L., De La Monte, S., Califano, S. and Wands, J. R. (2008), Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver. Hepatology Research, 38: 940–953. doi: 10.1111/j.1872-034X.2008.00336.x
Publication History
- Issue published online: 5 AUG 2008
- Article first published online: 10 MAR 2008
- Received 1 October 2007; revision 15 November 2007; accepted 29 December 2007.
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Keywords:
- ethanol;
- Frizzled;
- hepatocellular carcinoma;
- insulin receptor substrate;
- transgenic mice;
- WNT
Aim: Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression.
Methods: Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT)–Frizzled (FZD) pathways, given their known roles in HCC.
Results: In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl–asparaginyl β hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC.
Conclusion: In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation.