Impact of insulin resistance on the progression of chronic liver diseases
Impact of insulin resistance on the progression of chronic liver diseases
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DOI：
10.3892/ijmm_00000088
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发表时间：
2008-12-01
影响因子：
5.4
通讯作者：
Fukui, Hiroshi
中科院分区：
文献类型：
--
作者：
Kaji, Kosuke;Yoshiji, Hitoshi;Fukui, Hiroshi
近年来的研究表明，胰岛素抵抗（IR）与慢性肝病的进展密切相关。尽管人们对可能的机制知之甚少。本研究的目的是阐明IR对肥胖糖尿病大鼠肝纤维化和肝癌发生的影响。猪血清和二乙基亚硝胺（DEN）诱导的OLETF大鼠肝纤维化发展和谷胱甘肽- s -转移酶胎盘形态（GST-P）阳性肿瘤前病变均明显加速。分别。在纤维化实验中。OLETF大鼠u-平滑肌肌动蛋白阳性激活的肝星状细胞（hsc）也随着肝胶原含量和转化生长因子- β的增加而显著增加(1)。我们的体外研究表明，葡萄糖和胰岛素都能刺激活化的造血干细胞的增殖。联合治疗具有加性效应。在DEN模型中，新生血管在肝癌发生中起着关键作用。在OLETF大鼠中几乎与肿瘤前病变发展同步上调，是一种有效的血管生成因子。血管内皮生长因子。高糖和胰岛素也通过细胞外信号调节的激酶1/2磷酸化显著增强体外新生血管。与对活化的hsc的影响类似，这两种因素共存的影响比任何单一因素都更有效。总之，这些结果表明，在大鼠中，IR状态至少部分通过刺激活化的HSC增殖和肝脏新生血管来直接加速肝纤维化的发展和肝癌的发生。
Recent studies have revealed a close relationship between insulin resistance (IR) and the progression of chronic liver diseases. although relatively little is known regarding the possible mechanisms involved. The aim of this study was to elucidate the impact of IR on the development of liver fibrosis and hepatocarcinogenesis using obese diabetic Otsuka Lona-Evans Tokushima Fatty (OLETF) rats. Liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF rats, being induced by pig serum and diethylnitrosamine (DEN). respectively. In the fibrosis experiment. u-smooth muscle actin-positive activated hepatic stellate cells (HSCs) also significantly increased in OLETF rats along with augmentation of the hepatic collagen content and transforming growth factor-beta(1). Our in vitro study showed that both glucose and insulin stimulated the proliferation of activated HSCs. and the combination treatment exerted an additive effect. In the DEN model, neovascularization, which plays a pivotal role in hepatocarcinogenesis. was up-regulated in OLETF rats almost in parallel with pre-neoplastic lesion development and a potent angiogenic factor. vascular endothelial growth factor. High glucose and insulin also significantly augmented the in vitro neovascularization Via extracellular signal-regulated kinase 1/2 phosphorylation. Similar to the effect on the activated HSCs, co-existence of both factors exerted a more potent effect than either single factor. In conclusion, these results indicated that the IR status directly accelerated liver fibrosis development and hepatocarcinogenesis at least partly through the stimulation of activated HSC proliferation and hepatic neovascularization, respectively, in the rat.