1. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.
- Author
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Horie, 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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LIVER physiology , *PROTEIN metabolism , *ANIMAL experimentation , *ANTHROPOMETRY , *CELLULAR signal transduction , *COMPARATIVE studies , *EPITHELIAL cells , *ESTERASES , *FAT cells , *GENES , *GENETIC disorders , *GENETIC techniques , *HEPATITIS , *HEPATOCELLULAR carcinoma , *HOMEOSTASIS , *INSULIN , *LIPIDS , *LIPID metabolism disorders , *LIVER , *LIVER tumors , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *PHOSPHATASES , *PHOSPHORYLATION , *PROTEINS , *RESEARCH , *PHENOTYPES , *EVALUATION research , *CELL physiology - 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 (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. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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