Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
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DOI：
10.1172/jci200420513
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发表时间：
2004-06-01
影响因子：
15.9
通讯作者：
Nakano, T
中科院分区：
文献类型：
--
作者：
Horie, Y;Suzuki, A;Nakano, T
PTEN是一种在许多人类癌症中突变的肿瘤抑制基因，并且其表达在几乎一半的肝癌患者中减少或缺失。我们使用Cre-loxP系统在小鼠（AlbCrePten（flox/flox）小鼠）中产生Pten的肝细胞特异性无效突变。AlbCrePten（flox/flox）小鼠表现出大量肝肿大和脂肪肝伴甘油三酯蓄积，这是一种与人类非酒精性脂肪性肝炎相似的表型。在突变肝细胞中诱导脂肪细胞特异性基因，这意味着这些细胞的脂肪样转化。参与脂肪生成和P-氧化的基因也被诱导，可能是由于反式激活因子PPARgamma和SREBP 1c水平升高。重要的是，肝脏中Pten功能的丧失导致肿瘤发生，47%的AlbCrePten（flox/flox）肝脏在44周龄时发生肝细胞腺瘤。到74-78周龄时，100%的AlbCrePten（flox/ftox）肝脏显示腺瘤，66%患有肝细胞癌。AlbCrePten（flox/flox）小鼠也显示胰岛素超敏反应。在体外，AlbCrePten（flox/flox）肝细胞过度增殖，并表现出蛋白激酶B和MAPK异常激活的过度氧化。因此，Pten是肝脏中脂肪生成、葡萄糖代谢、肝细胞稳态和肿瘤发生的重要调节剂。
PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepadtis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and P-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% ofAlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% ofAlbCrePten(flox/ftox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.