Premium
Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate‐1 overexpression in liver
Author(s) -
Longato Lisa,
De La Monte Suzanne,
Califano Sophia,
Wands Jack R.
Publication year - 2008
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2008.00336.x
Subject(s) - irs1 , proliferating cell nuclear antigen , endocrinology , wnt signaling pathway , medicine , steatosis , inflammation , genetically modified mouse , transgene , cancer research , biology , insulin , insulin receptor , immunohistochemistry , signal transduction , microbiology and biotechnology , gene , insulin resistance , biochemistry
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.