Insulin resistance in experimental alcohol-induced liver disease
Insulin resistance in experimental alcohol-induced liver disease
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DOI：
10.1111/j.1440-1746.2008.05339.x
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发表时间：
2008-08-01
影响因子：
4.1
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
de la Monte, Suzanne M.;Yeon, Jong-Eun;Wands, Jack R.
背景和目的：慢性酒精消耗损害肝再生，部分原因是抑制胰岛素信号。这项研究的特点乙醇受损的胰岛素信号转导的机制和后果有关的氧化损伤和改变gene expression.Methods：Long-Evans大鼠喂养8周，含0%（对照）或37%乙醇（热量）的等热量液体饮食。肝脏用于检查组织病理学、氧化应激指数、胰岛素和胰岛素样生长因子（IGF）信号传导所需的基因表达、胰岛素应答基因表达，即甘油醛-3-磷酸脱氢酶（GAPDH）和乙酰天冬酰胺酰-β-羟化酶（AAH），以及与胰岛素、IGF-I和IGF-II受体的竞争性平衡结合。慢性乙醇暴露导致肝损伤，肝细胞脂肪变性、炎症、细胞凋亡增加，活化半胱天冬酶-3、8-羟基-2 '-脱氧鸟苷和4-羟基-2，3-壬烯醇的免疫反应性增加。这些影响与IGF-I受体，IGF-II，IGF-II受体的表达增加，IGF-I，AAH和GAPDH的表达，介导能量代谢和细胞运动/重塑，并减少结合到insulin receptor.Conclusions：慢性乙醇诱导的肝损伤导致胰岛素抵抗与抑制胰岛素反应基因所需的代谢，重塑和再生。相反，IGF-I和IGF-II信号传导机制保持相对保留，表明胰岛素调节的肝功能可能选择性地易受乙醇毒性作用的影响。
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.