TY - JOUR AU - Horie, Yasuo AU - Suzuki, Akira AU - Kataoka, Ei AU - Sasaki, Takehiko AU - Hamada, Koichi AU - Sasaki, Junko AU - Mizuno, Katsunori AU - Hasegawa, Go AU - Kishimoto, Hiroyuki AU - Iizuka, Masahiro AU - Naito, Makoto AU - Enomoto, Katsuhiko AU - Watanabe, Sumio AU - Mak, Tak Wah AU - Nakano, Toru T1 - Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas PY - 2004/06/15/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI20513 VL - 113 IS - 12 UR - https://doi.org/10.1172/JCI20513 SP - 1774 EP - 1783 PB - The American Society for Clinical Investigation ER -