Hepatocyte-specific Pten Deficiency Results in Steatohepatitis and Hepatocellular Carcinomas

J Clin Invest. 2004 Jun;113(12):1774-83. doi: 10.1172/JCI20513.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Gene Expression Regulation
  • Hepatitis / metabolism*
  • Hepatitis / pathology
  • Hepatocytes / cytology
  • Hepatocytes / physiology*
  • Homeostasis
  • Humans
  • In Situ Nick-End Labeling
  • Insulin / metabolism
  • Lipid Metabolism
  • Lipids / chemistry
  • Liver / chemistry
  • Liver / pathology
  • Liver / physiology*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • PTEN Phosphohydrolase
  • Phenotype
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Signal Transduction / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Insulin
  • Lipids
  • Tumor Suppressor Proteins
  • Phosphoric Monoester Hydrolases
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse