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Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice
Open accessAbstract
Hepatocyte nuclear factor 4α (HNF4α) regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism, and blood coagulation. In addition to its metabolic role, HNF4α is critical for hepatocyte differentiation, and loss of HNF4α is associated with hepatocellular carcinoma. The hepatocyte-specific Hnf4a knock-out mouse develops severe hepatomegaly and steatosis resulting in premature death, thereby limiting studies of the role of this transcription factor in the adult animal. In addition, gene compensation may complicate analysis of the phenotype of these mice. To overcome these issues, an acute Hnf4a knock-out mouse model was generated through use of the tamoxifen-inducible ErT2cre coupled to the serum albumin gene promoter. Microarray expression analysis revealed up-regulation of genes associated with proliferation and cell cycle control only in the acute liver-specific Hnf4α-null mouse. BrdU and ki67 staining confirmed extensive hepatocyte proliferation in this model. Proliferation was associated with induction of the hepatomitogen Bmp7 as well as reduced basal apoptotic activity. The p53/p63 apoptosis effector gene Perp was further identified as a direct HNF4α target gene. These data suggest that HNF4α maintains hepatocyte differentiation in the adult healthy liver, and its loss may directly contribute to hepatocellular carcinoma development, thus indicating this factor as a possible liver tumor suppressor gene.
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“In liver, HNF4A is required for normal development (2), including morphogenesis (3) and differentiation (4), and controls other TFs critical in liver cell fate as well as genes necessary for hepatocyte functions.”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [4]
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Metadata
- Authors
- Bonzo, J. A., Ferry, C. H., Matsubara, T., Kim, J.-H., & Gonzalez, F. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gonzalez, Frank J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 287
- Issue
- 10
- Pages
- 7345-7356
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3293558
- OpenAlex
- W2016456139
- Cited by
- 193
- References
- 60
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 19 · 2021: 12 · 2020: 20 · 2019: 12 · 2018: 16 · 2017: 19 · 2016: 13 · 2015: 15 · 2014: 15 · 2013: 11 · 2012: 4
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- HNF4α, hepatocyte proliferation, hepatocyte differentiation, hepatocellular carcinoma, tamoxifen-inducible Cre, BMP-7, apoptosis, PERP, transcription factors, steatosis, hepatomegaly
- MeSH terms
- Animals, Cell Cycle, Cell Differentiation, Disease Models, Animal, Fatty Liver, Carcinoma, Hepatocellular, Hepatomegaly, Liver Neoplasms, Membrane Proteins, Organ Specificity, Phosphoproteins, Trans-Activators, Tumor Suppressor Protein p53, Mice, Knockout, Hepatocytes, Mice, Hepatocyte Nuclear Factor 4, Bone Morphogenetic Protein 7
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