Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice
Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice
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DOI：
10.1016/s0016-5085(03)00276-2
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发表时间：
2003-05-01
期刊：
影响因子：
29.4
通讯作者：
Kaplowitz, N
中科院分区：
文献类型：
--
作者：
Ji, C;Kaplowitz, N
背景与目的：酒精诱导的高同型半胱氨酸血症在大鼠和人类中已有报道。高同型半胱氨酸血症与内质网应激相关，导致内质网依赖性细胞凋亡激活或脂质合成上调。在灌胃酒精小鼠模型上研究了这种新的内质网应激机制。方法：采用cDNA微阵列、RT-PCR和Western blots分析酒精对基因表达的影响，为期6周。肝组织染色及TUNEL检查肝损伤情况。结果：观察到脂肪肝，肝坏死、炎症和凋亡增加，高同型半胱氨酸血症。在1176个毒理学相关基因中，葡萄糖调节蛋白（GRP-78和-94）、生长阻滞/DNA损伤诱导蛋白153 （CHOP/GADD153）和指示内质网应激反应的caspase-12是酒精应答基因。甾醇调节元件结合蛋白（SREBP-1）和HMG-CoA还原酶也随着酒精的添加而增强。RT-PCR和选择性Western blot证实了酒精诱导内质网应激相关凋亡和脂质合成基因的表达。在酒精饮食中添加0.5%和最大1.5%甜菜碱可将血浆同型半胱氨酸升高水平降低54%和80%以上，同时肝脏脂质和内质网应激反应降低。甜菜碱没有减弱乙醇诱导的肿瘤坏死因子α或CD: 14mrna的升高。结论：酒精可能通过同型半胱氨酸诱导的内质网应激调节慢性酒精性小鼠肝脏的凋亡和脂肪合成基因表达，甜菜碱或其他方法纠正高同型半胱氨酸血症可能有助于预防酒精性肝病。
Background & Aims: Alcohol-induced hyperhomocysteinemia has been reported in rats and humans. Hyperhomocysteinemia has been associated with endoplasmic reticulum (ER) stress leading to the activation of ER-dependent apoptosis or up-regulation of lipid synthesis. This novel ER stress mechanism of alcoholic liver injury was studied in the model of intragastric alcohol-fed mice. Methods: Effects of alcohol on gene expression were analyzed using cDNA microarrays, RT-PCR, and Western blots over a period of 6 weeks. Liver injury was examined by histologic staining and TUNEL. Results: We observed fatty liver, increased hepatic necroinflammation and apoptosis, and hyperhomocysteinemia. Of 1176 toxicology-related genes, glucose-regulated proteins (GRP-78 and -94), growth arrest/DNA damage-inducible protein 153 (CHOP/GADD153), and caspase-12 indicative of an ER stress response were among the alcohol-responsive genes. Sterol regulatory element binding protein (SREBP-1) and HMG-CoA reductase also were enhanced with alcohol administration. RT-PCR and selective Western blots confirmed the alcohol-induced expression of ER stress-related apoptosis and lipid synthesis genes. Addition of 0.5% and maximal 1.5% betaine to the alcohol diet reduced the elevated level of plasma homocysteine by 54% and more than 80% accompanied by a decrease in hepatic lipids and ER stress response. Betaine did not attenuate the ethanol-induced increase in tumor necrosis factor alpha or CD:14 mRNA. Conclusions: The results strongly suggest that alcohol may modulate both apoptotic and fat synthetic gene expression through homocysteine-induced ER stress in chronic alcoholic mouse liver and that correction of hyperhomocysteinemia by betaine or other approaches may be useful to prevent alcoholic liver disease.