Long-Term Ethanol Consumption Promotes Hepatic Tumorigenesis but Impairs Normal Hepatocyte Proliferation in Rats
Long-Term Ethanol Consumption Promotes Hepatic Tumorigenesis but Impairs Normal Hepatocyte Proliferation in Rats
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DOI：
10.3945/jn.110.136531
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发表时间：
2011-06-01
影响因子：
4.2
通讯作者：
Wang, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Chavez, Pollyanna R. G.;Lian, Fuzhi;Wang, Xiang-Dong
长期和过度饮酒与包括肝脏在内的几种癌症的风险增加有关;然而，动物模型研究尚未最终确定乙醇是否在肝脏肿瘤发生中作为肿瘤促进剂。我们研究了在大鼠模型中，长期饮酒是否可以作为二乙基亚硝胺（DEN）启动后的肝肿瘤促进剂。雄性Sprague-Dawley大鼠注射20毫克DEN/公斤体重1周前引入的乙醇液体饮食或等能控制液体饮食。在6个月和10个月后评估肝脏病理学病变、肝细胞增殖、凋亡、PPAR α和PPAR γ以及血浆胰岛素样生长因子1（IGF-1）水平。平均体重和肝脏重量，血浆IGF-1浓度，肝脏增殖细胞核抗原和Ki-67的表达，和细胞周期蛋白D1在乙醇喂养的大鼠都显着低于治疗后10个月与对照组大鼠相比。此外，在长期治疗后，酒精喂养大鼠的肝脏过氧化物酶体增殖物激活受体γ蛋白水平显著升高，而不是过氧化物酶体增殖物激活受体α。虽然乙醇喂养也导致显着减少改变肝病灶，肝细胞腺瘤检测乙醇喂养大鼠在10个月，但在对照组大鼠给予相同剂量的DEN。总之，这些结果表明，慢性，过量的乙醇消耗损害正常的肝细胞增殖，这是与降低IGF-1水平，但促进肝癌发生。J. Nutr. 141：1049-1055，2011.
Chronic and excessive alcohol consumption has been related to an increased risk of several cancers, including that of the liver; however, studies in animal models have yet to conclusively determine whether ethanol acts as a tumor promoter in hepatic tumorigenesis. We examined whether prolonged alcohol consumption could act as a hepatic tumor promoter after initiation by diethylnitrosamine (DEN) in a rat model. Male Sprague-Dawley rats were injected with 20 mg DEN/kg body weight 1 wk before introduction of either an ethanol liquid diet or an isoenergic control liquid diet. Hepatic pathological lesions, hepatocyte proliferation, apoptosis, PPAR alpha and PPAR gamma, and plasma insulin-like growth factor 1 IGF-1) levels were assessed after 6 and 10 mo. Mean body and liver weights, plasma IGF-1 concentration, hepatic expressions of proliferating cellular nuclear antigen and Ki-67, and cyclin D1 in ethanol-fed rats were all significantly lower after 10 mo of treatment compared with control rats. In addition, levels of hepatic PPAR gamma protein, not PPAR alpha, were significantly higher in the ethanol-fed rats after prolonged treatment. Although ethanol feeding also resulted in significantly fewer altered hepatic foci, hepatocellular adenoma was detected in ethanol-fed rats at 10 mo, but not in control rats given the same dose of DEN. Together, these results indicate that chronic, excessive ethanol consumption impairs normal hepatocyte proliferation, which is associated with reduced IGF-1 levels, but promotes hepatic carcinogenesis. J. Nutr. 141: 1049-1055, 2011.