Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver

Journal Article (Journal Article)

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. © 2008 The Japan Society of Hepatology.

Full Text

Duke Authors

Cited Authors

  • Longato, L; De La Monte, S; Califano, S; Wands, JR

Published Date

  • August 13, 2008

Published In

Volume / Issue

  • 38 / 9

Start / End Page

  • 940 - 953

International Standard Serial Number (ISSN)

  • 1386-6346

Digital Object Identifier (DOI)

  • 10.1111/j.1872-034X.2008.00336.x

Citation Source

  • Scopus