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/jci20513
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发表时间：
2004-06
期刊：
影响因子：
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通讯作者：
Y. Horie;A. Suzuki;E. Kataoka;Takehiko Sasaki;K. Hamada;J. Sasaki;K. Mizuno;G. Hasegawa;
中科院分区：
文献类型：
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作者：
Y. Horie;A. Suzuki;E. Kataoka;Takehiko Sasaki;K. Hamada;J. Sasaki;K. Mizuno;G. Hasegawa;
PTEN是一种肿瘤抑制基因，在许多人类癌症中发生突变，在几乎一半的肝癌患者中表达降低或缺失。我们使用Cre-loxP系统在小鼠(AlbCrePten(FLOX/FLOX)小鼠)中产生了肝细胞特异性的Pten零突变。AlbCrePten(FLOX/FLOX)小鼠表现出大量肝肿大和脂肪性肝炎，并伴有甘油三酯积聚，这是一种类似于人类非酒精性脂肪性肝炎的表型。在突变的肝细胞中诱导了脂肪细胞特异性基因，这意味着这些细胞发生了类似脂肪的转化。参与脂肪生成和β-氧化的基因也被诱导，可能是由于反式激活因子PPARGamma和SREBP1c水平升高所致。重要的是，肝脏中Pten功能的丧失导致了肿瘤的发生，47%的AlbCrePten(FLOX/FLOX)肝脏在44周龄时发展为肝细胞腺瘤。到74-78周龄，100%的AlbCrePten(FLOX/FLOX)肝脏出现腺瘤，66%出现肝细胞癌。AlbCrePten(FLOX/FLOX)小鼠也表现出胰岛素过敏。在体外，AlbCrePten(FLOX/FLOX)肝细胞过度增殖，表现为过度氧化，蛋白激酶B和MAPK异常激活。因此，PTEN是脂肪生成、葡萄糖代谢、肝细胞动态平衡和肝脏肿瘤发生的重要调节因子。
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 steatohepatitis 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 beta-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% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) 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.