Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis
Open accessAbstract
The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1alpha [HNF1alpha], -1beta, -3alpha, -3beta, -3gamma, -4alpha, and -6 and members of the c/ebp family). Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1alpha-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4alpha-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4alpha is indispensable for hepatocyte differentiation. However, the function of HNF4alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.
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In adult mice, loss of HNF4A affects lipid homeostasis leading to liver steatosis.
“HNF4A deficiency in mouse embryonic liver causes failure in hepatocyte differentiation (2), while in adult mice loss of HNF4A affects lipid homeostasis leading to liver steatosis (5).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [5]
HNF4A is a key TF in liver as its loss is associated with transcriptional repression of genes.
“HNF4A is a key TF in liver as its loss is associated with transcriptional repression of genes (5, 10).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [5]
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Cites
SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4
Wang, J.-C., Stafford, J. M., & Granner, D. K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.47.30847 · Cited by 147 · see citing works
Functional Association between CBP and HNF4 inTrans-activation
Yoshida, E., Aratani, S., Itou, H., Miyagishi, M., Takiguchi, M., Osumu, T., Murakami, K., & Fukamizu, A. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7871 · Cited by 104 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- [26]26. Laird, P. W., A. Zijderveld, K. Linders, M. A. Rudnicki, R. Jaenisch, and A. Berns. 1991. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 19: 4293. Alt, and H. Westphal. 1996. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA 93: 5860-5865.
- [47]47. Sladek, F. M. 1994. Hepatocyte nuclear factor 4, p. 207-230. In F. Tronche and M. Yaniv (ed.), Liver gene expression. R. G. Landes Company, Austin, Tex.
- [63]63. Weng, W., and J. L. Breslow. 1996. Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc. Natl. Acad. Sci. USA 93: 14788-14794.
- [66]66. Yakar, S., J. L. Liu, B. Stannard, A. Butler, D. Accili, B. Sauer, and D. LeRoith. 1999. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 96: 7324-7329.
Cited by
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Hindorff, L. A., Sethupathy, P., Junkins, H. A., Ramos, E. M., Mehta, J. P., Collins, F. S., & Manolio, T. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903103106 · Cited by 4,013 · see citing works
Common variants at 30 loci contribute to polygenic dyslipidemia
Kathiresan, S., Willer, C. J., Peloso, G. M., Demissie, S., Musunuru, K., Schadt, E. E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., et al. (2009) · Nature Genetics · doi:10.1038/ng.291 · Cited by 1,364 · see citing works
Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network
Bookout, A. L., Jeong, Y., Downes, M., Yu, R. T., Evans, R. M., & Mangelsdorf, D. J. (2006) · Cell · doi:10.1016/j.cell.2006.06.049 · Cited by 1,015 · see citing works
Bile salt transporters: molecular characterization, function, and regulation
Trauner, M., & Boyer, J. L. (2003) · Physiological Reviews · doi:10.1152/physrev.00027.2002 · Cited by 999 · see citing works
Bile Acid Transporters: Structure, Function, Regulation and Pathophysiological Implications
Alrefai, W. A., & Gill, R. K. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9289-1 · Cited by 500 · see citing works
Simcox, J., Geoghegan, G., Maschek, J. A., Bensard, C. L., Pasquali, M., Miao, R., Lee, S., Jiang, L., Huck, I., Kershaw, E. E., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.006 · Cited by 277 · see citing works
Henderson, C. J., Otto, D. M. E., Carrie, D., Magnuson, M. A., McLaren, A. W., Rosewell, I., & Wolf, C. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212087200 · Cited by 258 · see citing works
Martin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J. Q., & Quarles, L. D. (2011) · The FASEB Journal · doi:10.1096/fj.10-177816 · Cited by 254 · see citing works
Courselaud, B., Pigeon, C., Inoue, Y., Inoue, J., Gonzalez, F. J., Leroyer, P., Gilot, D., Boudjema, K., Guguen-Guillouzo, C., Brissot, P., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202653200 · Cited by 245 · see citing works
Self-citationWolska, A., Dunbar, R. L., Freeman, L. A., Ueda, M., Amar, M. J., Sviridov, D. O., & Remaley, A. T. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.10.025 · Cited by 231 · see citing works
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Bonzo, J. A., Ferry, C. H., Matsubara, T., Kim, J.-H., & Gonzalez, F. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.334599 · Cited by 193 · see citing works
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Nishikawa, T., Bell, A., Brooks, J. M., Setoyama, K., Melis, M., Han, B., Fukumitsu, K., Handa, K., Tian, J., Kaestner, K. H., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73137 · Cited by 124 · see citing works
Hoffman, B. G., Robertson, G., Zavaglia, B., Beach, M., Cullum, R., Lee, S., Soukhatcheva, G., Li, L., Wederell, E. D., Thiessen, N., et al. (2010) · Genome Research · doi:10.1101/gr.104356.109 · Cited by 115 · see citing works
“HNF4A is not essential for the early phases of liver development, but controls many genes that are vital for adult liver functions, and is considered a central regulator of hepatocyte differentiation and function (Hayhurst et al. 2001; Battle et al. 2006).”
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Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113 · see citing works
“A later depletion of HNF4A by 6 weeks postpartum results in disrupted liver architecture; changes in serum, lipid, and urea levels; and ultimately a 70% mortality rate by 8 weeks of age (Hayhurst et al., 2001).”
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Zhang, Y., Yin, L., Anderson, J., Ma, H., Gonzalez, F. J., Willson, T. M., & Edwards, P. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.083899 · Cited by 112 · see citing works
Self-citationCellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A. (2021) · Genome Research · doi:10.1101/gr.267013.120 · Cited by 102 · see citing works
Akiyama, T. E., Lambert, G., Nicol, C. J., Matsusue, K., Peters, J. M., Brewer, H. B., & Gonzalez, F. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312802200 · Cited by 97 · see citing works
Self-citationThakur, A., Wong, J. C. H., Wang, E. Y., Lotto, J., Kim, D., Cheng, J., Mingay, M., Cullum, R., Moudgil, V., Ahmed, N., et al. (2019) · Hepatology · doi:10.1002/hep.30631 · Cited by 75 · see citing works
“HNF4A is a key TF in liver given that its loss is associated with transcriptional repression of genes.(5,10) Although various TFs were shown to regulate gene expression by influencing histone(24,37) and DNA modifications at gene-regulatory regions,(24,37,38) the role of HNF4A in epigenetic-mediated gene regulation in…”
BackgroundSelf-citationEeckhoute, J. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh581 · Cited by 71 · see citing works
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Yan, J., Chen, B., Lu, J., & Xie, W. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.102 · Cited by 69 · see citing works
Beaudry, J.-B., Pierreux, C. E., Hayhurst, G. P., Plumb-Rudewiez, N., Weiss, M. C., Rousseau, G. G., & Lemaigre, F. P. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02445-05 · Cited by 56 · see citing works
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Goel, C., Monga, S. P., & Nejak-Bowen, K. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.09.007 · Cited by 53 · see citing works
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Rufibach, L. E., Duncan, S. A., Battle, M., & Deeb, S. S. (2006) · Journal of Lipid Research · doi:10.1194/jlr.m600082-jlr200 · Cited by 52 · see citing works
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Lotto, J., Stephan, T. L., & Hoodless, P. A. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00775-2 · Cited by 47 · see citing works
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Chen, L., Cao, W., Aita, R., Aldea, D., Flores, J., Gao, N., Bonder, E. M., Ellison, C. E., & Verzi, M. P. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108679 · Cited by 27 · see citing works
Signalling pathways and transcriptional regulators orchestrating liver development and cancer
Campbell, S. A., Stephan, T. L., Lotto, J., Cullum, R., Drissler, S., & Hoodless, P. A. (2021) · Development · doi:10.1242/dev.199814 · Cited by 22 · see citing works
Ramella Gal, I., Arez, F., Correia, I. P., Domenici, G., Fernandes, S., Silva, G., Saldanha, I., Duarte, N., Freitas, C., Alves, P. M., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-31044-8 · Cited by 4 · see citing works
- Authors
- Hayhurst, G. P., Lee, Y.-H., Lambert, G., Ward, J. M., & Gonzalez, F. J.
- Affiliations
- National Cancer Institute (UA)
- National Institutes of Health (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-02
- Volume
- 21
- Issue
- 4
- Pages
- 1393-1403
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC99591
- OpenAlex
- W2161197995
- Cited by
- 1,107
- References
- 2
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 36 · 2023: 41 · 2022: 43 · 2021: 49 · 2020: 52 · 2019: 40 · 2018: 42 · 2017: 36 · 2016: 44 · 2015: 43 · 2014: 33 · 2013: 44 · 2012: 49
- FWCI
- 37.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- HNF4α, hepatocyte differentiation, hepatic lipid homeostasis, hepatic gene expression, very low density lipoprotein secretion, apolipoprotein B, microsomal triglyceride transfer protein, hepatic cholesterol uptake, scavenger receptor BI, bile acid transport, serum cholesterol, serum triglycerides, bile acids, conditional knockout mice
- MeSH terms
- Animals, Base Sequence, Bile Acids and Salts, Biological Transport, Active, Cell Differentiation, DNA-Binding Proteins, Hepatomegaly, Homeostasis, Lipids, Liver, Liver Glycogen, Mice, Inbred C57BL, Phenotype, Phosphoproteins, Transcription Factors, Gene Expression, DNA Primers, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Gene Targeting, Lipid Metabolism, Mice, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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