Insulin resistance in experimental alcohol-induced liver disease

Suzanne M. De La Monte, Jong Eun Yeon, Ming Tong, Lisa Longato, Rajeev Chaudhry, Mao Yin Pang, Kevin Duan, Jack R. Wands

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Background and Aim: Chronic ethanol consumption impairs liver regeneration due, in part, to inhibition of insulin signaling. This study characterizes the mechanisms and consequences of ethanol-impaired insulin signaling in relation to oxidative injury and altered gene expression. Methods: Long-Evans rats were fed for 8 weeks with isocaloric liquid diets containing 0% (control) or 37% ethanol (caloric content). Livers were used to examine histopathology, indices of oxidative stress, gene expression required for insulin and insulin-like growth factor (IGF) signaling, insulin-responsive gene expression, i.e. glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and aspartyl-asparaginyl- β-hydroxylase (AAH), and competitive equilibrium binding to the insulin, IGF-I, and IGF-II receptors. Results: Chronic ethanol exposure caused liver injury with increased hepatocellular steatosis, inflammation, apoptosis, and increased immunoreactivity for activated caspase-3, 8-hydroxy-2′- deoxyguanosine, and 4-hydroxy-2,3-nonenol. These effects were associated with increased expression of IGF-I receptor, IGF-II, and IGF-II receptor, and expression of IGF-I, AAH, and GAPDH, which mediate energy metabolism and cell motility/remodeling, and reduced binding to the insulin receptor. Conclusions: Chronic ethanol-induced liver injury causes insulin resistance with inhibition of insulin-responsive genes needed for metabolism, remodeling, and regeneration. In contrast, the IGF-I and IGF-II signaling mechanisms remain relatively preserved, suggesting that insulin-regulated hepatic functions may be selectively vulnerable to the toxic effects of ethanol.

Original languageEnglish
Pages (from-to)e477-e486
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume23
Issue number8 PART2
DOIs
Publication statusPublished - 2008 Aug
Externally publishedYes

Keywords

  • Alcoholic liver disease
  • Apoptosis
  • Aspartyl-asparaginyl-β-hydroxylase
  • DNA damage
  • Insulin resistance
  • Oxidative stress
  • Receptor binding

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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