Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.
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.
Horie
Yasuo
Y
Department of Gastroenterology, Akita University School of Medicine, Akita, Japan.
Suzuki
Akira
A
Kataoka
Ei
E
Sasaki
Takehiko
T
Hamada
Koichi
K
Sasaki
Junko
J
Mizuno
Katsunori
K
Hasegawa
Go
G
Kishimoto
Hiroyuki
H
Iizuka
Masahiro
M
Naito
Makoto
M
Enomoto
Katsuhiko
K
Watanabe
Sumio
S
Mak
Tak Wah
TW
Nakano
Toru
T
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D051059:PTEN Phosphohydrolase; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D008055:Lipids; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse