Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage.
Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage.
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DOI：
10.18632/oncotarget.19978
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发表时间：
2017-09-19
期刊：
影响因子：
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通讯作者：
Shimizu M
中科院分区：
文献类型：
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作者：
Ideta T;Shirakami Y;Ohnishi M;Maruta A;Obara K;Miyazaki T;Kochi T;Sakai H;Tomita H;Tanaka T;Blaner WS;Shimizu M
非酒精性脂肪性肝病已成为慢性肝病最常见的原因之一，可发展为更严重的形式，非酒精性脂肪性肝炎，导致肝硬化和肝细胞癌。虽然肝脏类维生素A储存在肝病发展过程中逐渐丢失，但这如何影响脂肪性肝炎及其相关的肝癌发生尚不清楚。为了研究这些，我们使用皮下注射链脲佐菌素（0.2毫克/人）和高脂饮食诱导脂肪性肝炎和肝肿瘤发生的卵磷脂：视黄醇酰基转移酶缺陷小鼠（n = 10），缺乏存储在肝脏中的类维生素A，和对照小鼠（n = 12）。在实验结束时（16周龄），与对照组相比，突变小鼠的肝肿瘤发展受到显著抑制。在突变小鼠中观察到血清丙氨酸氨基转移酶水平降低和肝脏细胞周期蛋白D1水平降低。突变小鼠表现出视黄酸反应基因，包括p21水平的增加，并降低氧化应激的血清和肝脏标志物的评价。我们的研究结果与以下结论一致：突变小鼠对脂肪性肝炎相关的肝脏肿瘤发生不太敏感，这是由于类维生素A信号转导增加，伴随着p21表达上调和氧化应激减弱。
Non-alcoholic fatty liver disease has become one of the most common causes of chronic liver disease that can develop into a more serious form, non-alcoholic steatohepatitis, leading to liver cirrhosis and hepatocellular carcinoma. Although hepatic retinoid stores are progressively lost during the development of liver disease, how this affects steatohepatitis and its related hepatocarcinogenesis is unknown. In order to investigate these, we used subcutaneous injection of streptozotocin (0.2 mg/body) and high-fat diet to induce steatohepatitis and hepatic tumorigenesis in lecithin:retinol acyltransferase -deficient mice (n = 10), which lack stored retinoid in the liver, and control mice (n = 12). At the termination of the experiment (16 weeks of age), the development of hepatic tumors was significantly suppressed in mutant mice compared to controls. Lower serum levels of alanine aminotransferase and decreased hepatic levels of cyclin D1 were observed in mutant mice. Mutant mice exhibited increased levels of retinoic acid-responsive genes, including p21, and decreased oxidative stress as evaluated by serum and liver markers. Our findings are consistent with the conclusion that mutant mice are less susceptible to steatohepatitis-related liver tumorigenesis due to increased retinoid signaling, which is accompanied by up-regulated p21 expression and attenuated oxidative stress.