PTEN公司
生物
脂肪性肝炎
肝细胞
内科学
脂肪生成
内分泌学
癌变
癌症研究
脂肪变性
脂肪肝
PI3K/AKT/mTOR通路
脂质代谢
癌症
医学
信号转导
细胞生物学
生物化学
疾病
体外
作者
Yasuo Horie,Akira Suzuki,Ei Kataoka,Takehiko Sasaki,Koichi Hamada,Junko Sasaki,Katsunori Mizuno,Go Hasegawa,Hiroyuki Kishimoto,Masahiro Iizuka,Makoto Naito,Katsuhiko Enomoto,Sumio Watanabe,Tak W. Mak,Toru Nakano
摘要
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 (AlbCrePtenflox/flox mice). AlbCrePtenflox/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 β-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARγ and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePtenflox/flox livers developing liver cell adenomas by 44 weeks of age. By 74–78 weeks of age, 100% of AlbCrePtenflox/flox livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePtenflox/flox mice also showed insulin hypersensitivity. In vitro, AlbCrePtenflox/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.
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