Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.

Authors: Horie, Y  Suzuki, A  Kataoka, E  Sasaki, T  Hamada, K  Sasaki, J  Mizuno, K  Hasegawa, G  Kishimoto, H  Iizuka, M  Naito, M  Enomoto, K  Watanabe, S  Mak, TW  Nakano, T 
Citation: Horie Y, etal., J Clin Invest 2004 Jun;113(12):1774-83.
Pubmed: (View Article at PubMed) PMID:15199412
DOI: Full-text: DOI:10.1172/JCI20513

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.


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CRRD Object Information
CRRD ID: 1302555
Created: 2004-10-13
Species: All species
Last Modified: 2004-10-13
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.