Cited by 205Liver physiology and pathologyHepatocellular Carcinoma Treatment and PrognosisWnt/β-catenin signaling in development and cancer

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Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice

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Bonzo, Jessica A., Ferry, Christina H., Matsubara, Tsutomu, Kim, Jung-Hwan, Gonzalez, Frank J.·2012·Journal of Biological Chemistry

DOI 10.1074/jbc.m111.334599PMC PMC3293558

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Abstract

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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Telomere dysfunction represses HNF4α leading to impaired hepatocyte development and functionPreprint
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Regulation of Lipoprotein Lipase Activity : an In-vitro Study of a Complex and Dynamic System
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Direct reprogramming of adult hepatocytes to generate LGR5+ endodermal progenitorPreprint
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Gd-EOB-DTPA-enhanced MRI in Hepatocellular Carcinoma : Molecular and Genetic Background
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Additional file 11 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605055
Additional file 2 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605028
Additional file 5 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lü, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881329
Additional file 8 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605046
Additional file 7 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605043
Additional file 10 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605052
Additional file 12 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605058
Additional file 3 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605031
Additional file 5 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605037
Additional file 4 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605034
Additional file 9 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605049
Additional file 6 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605040
Differentially Regulated pathways of Potential Importance for Treatment Response and Cardiac Toxicity after Administration of Doxorubicine to BC Patients
Olsen, T. (2012) · BIBSYS Brage (BIBSYS (Norway))
Additional file 3 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881323
Additional file 4 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881326
Additional file 7 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881335
Additional file 1 of Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia
Rutten, M. G. S., Lei, Y., Hoogerland, J. H., Bloks, V. W., Yang, H., Bos, T., Krishnamurthy, K. A., Bleeker, A., Koster, M. H., Thomas, R., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26584218
Additional file 1 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881317
Additional file 6 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881332
Additional file 2 of Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet
Lu, H., Lei, X., Winkler, R., John, S., Kumar, D., Li, W., & Alnouti, Y. (2022) · Figshare · doi:10.6084/m9.figshare.19881320
Additional file 1 of Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Chen, S., Liu, S., Shi, S., Jiang, Y., Cao, M., Tang, Y., Li, W., Liu, J., Fang, L., Yu, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22605025
Inflammation-Driven Downregulation of CYP2E1 Is Associated with Attenuated Diethylnitrosamine (DEN)-Induced Hepatocarcinogenesis
Tsuchiya, Y., Sotomaru, Y., Kanai, A., Maeda, S., & Kamata, H. (2026) · Cells · doi:10.3390/cells15060546

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.
ORCID: Bonzo, Jessica A.
Matsubara, Tsutomu
Kim, Jung-Hwan
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)
DOI: 10.1074/jbc.m111.334599
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 3123 d)
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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Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice

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