1. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.
- Author
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Hone, Yasuo, Suzuki, Akira, Kataoka, Ei, Sasaki, Takehiko, Hamada, Koichi, Sasaki, Junko, Mizuno, Katsunori, Hasegawa, Go, Kishimoto, Hiroyuki, Iizuka, Masahiro, Naito, Makoto, Enomoto, Katsuhiko, Watanabe, Sumio, Mak, Tak Wah, and Nakano, Toru
- Subjects
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CANCER patients , *GENES , *LIVER cells , *GROWTH factors , *GENETICS , *CYTOKINES - Abstract
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/floxmice). 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 AlbCre tenflox/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. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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