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Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.
- Source :
-
Journal of Clinical Investigation . Jun2004, Vol. 113 Issue 12, p1774-1783. 10p. 5 Color Photographs, 2 Black and White Photographs, 1 Diagram, 1 Chart, 2 Graphs. - Publication Year :
- 2004
-
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/floxmice). 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 AlbCre tenflox/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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CANCER patients
*GENES
*LIVER cells
*GROWTH factors
*GENETICS
*CYTOKINES
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 113
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 13443019
- Full Text :
- https://doi.org/10.1172/JCI200420513