Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
Yasuo Horie, … , Tak Wah Mak, Toru Nakano
Yasuo Horie, … , Tak Wah Mak, Toru Nakano
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1774-1783. https://doi.org/10.1172/JCI20513.
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Article Oncology

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

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/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.

Authors

Yasuo Horie, Akira Suzuki, Ei Kataoka, Takehiko Sasaki, Koichi Hamada, Junko Sasaki, Katsunori Mizuno, Go Hasegawa, Hiroyuki Kishimoto, Masahiro Iizuka, Makoto Naito, Katsuhiko Enomoto, Sumio Watanabe, Tak Wah Mak, Toru Nakano

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Steatohepatitis in AlbCrePtenflox/flox mice. (A) Histological analyses o...
Steatohepatitis in AlbCrePtenflox/flox mice. (A) Histological analyses of liver sections from +/+ and flox/flox mice sacrificed at 10 weeks of age. The first and second rows show a lower (∞10) and higher (∞400) magnification of H&E-stained livers, respectively. Lipid accumulation was observed around the central vein area (C), whereas the periportal vein area (P) was almost intact. Lipid accumulation was confirmed by Oil-red O staining (third row). Liver fibrosis was not evident as determined by Azan staining (fourth row). Lipid accumulation was also confirmed by electron microscopy (fifth row). (B) Histological analyses of liver sections of +/+, flox/+, and flox/flox mice (without precancerous tumors) sacrificed at 40 weeks of age. The first and second rows show a lower (∞10) and higher (∞400) magnification of H&E-stained liver sections, respectively. The third row (left) shows an accumulation of lipid in the mutant liver that resembles adipocytes in a fat tissue. Additional features of mutant livers were steatohepatitis and Mallory bodies (third row right, arrows), sinusoidal fibrogenic changes (fourth row left), and an accumulation of inflammatory cells (fourth row right). Focal lipid-laden hepatocytes within diffuse mild fatty changes were noted in the livers of some flox/+ mice (fifth row).