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Article: Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

TitleHepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
Authors
Issue Date2004
Citation
Journal of Clinical Investigation, 2004, v. 113, n. 12, p. 1774-1783 How to Cite?
AbstractPTEN 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 AlbCrePten flox/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, AlbCrePten flox/flox hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pren is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.
Persistent Identifierhttp://hdl.handle.net/10722/293089
ISSN
2023 Impact Factor: 13.3
2023 SCImago Journal Rankings: 4.833
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHorie, Yasuo-
dc.contributor.authorSuzuki, Akira-
dc.contributor.authorKataoka, Ei-
dc.contributor.authorSasaki, Takehiko-
dc.contributor.authorHamada, Koichi-
dc.contributor.authorSasaki, Junko-
dc.contributor.authorMizuno, Katsunori-
dc.contributor.authorHasegawa, Go-
dc.contributor.authorKishimoto, Hiroyuki-
dc.contributor.authorIizuka, Masahiro-
dc.contributor.authorNaito, Makoto-
dc.contributor.authorEnomoto, Katsuhiko-
dc.contributor.authorWatanabe, Sumio-
dc.contributor.authorMak, Tak Wah-
dc.contributor.authorNakano, Toru-
dc.date.accessioned2020-11-17T14:57:51Z-
dc.date.available2020-11-17T14:57:51Z-
dc.date.issued2004-
dc.identifier.citationJournal of Clinical Investigation, 2004, v. 113, n. 12, p. 1774-1783-
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10722/293089-
dc.description.abstractPTEN 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 AlbCrePten flox/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, AlbCrePten flox/flox hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pren is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.-
dc.languageeng-
dc.relation.ispartofJournal of Clinical Investigation-
dc.titleHepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1172/JCI20513-
dc.identifier.pmid15199412-
dc.identifier.pmcidPMC420505-
dc.identifier.scopuseid_2-s2.0-85047694402-
dc.identifier.volume113-
dc.identifier.issue12-
dc.identifier.spage1774-
dc.identifier.epage1783-
dc.identifier.isiWOS:000222045300015-
dc.identifier.issnl0021-9738-

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