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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

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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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Figure 1

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Generation of hepatocyte-specific Pten-deficient (AlbCrePtenflox/flox) m...
Generation of hepatocyte-specific Pten-deficient (AlbCrePtenflox/flox) mice. (A) Targeting strategy. Exons of the murine Pten gene are represented by filled boxes, loxP sites by filled arrowheads. The probe used to analyze Southern blots is indicated and has been described previously (14). The floxed (Ptenflox) and deleted (PtenØ) alleles are shown. (B) Genomic Southern blot. DNA (20 ∝g) extracted from total liver cells of the indicated genotypes was digested with HindIII. The vast majority of total liver cells from AlbCrePtenflox/flox mice showed deletion of the Pten gene. (C) Western blot analysis of Pten protein expression by total liver cells of the indicated genotype. Actin, loading control. Liver samples were obtained from 8-week-old mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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