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- Title
Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.
- Authors
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; Nakano, Toru
- 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.
- Subjects
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
- Publication
Journal of Clinical Investigation, 2004, Vol 113, Issue 11, p1774
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/jci20513