期刊
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
卷 23, 期 8, 页码 E477-E486出版社
WILEY
DOI: 10.1111/j.1440-1746.2008.05339.x
关键词
alcoholic liver disease; apoptosis; aspartyl-asparaginyl-beta-hydroxylase; DNA damage; insulin resistance; oxidative stress; receptor binding
资金
- NIAAA NIH HHS [R37 AA002666, AA11431, K24 AA016126, AA-16126, AA02666, R37 AA011431, AA02169, R01 AA011431, R56 AA011431, R01 AA002666, R01 AA012908, AA12908] Funding Source: Medline
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-beta-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.
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