The hippo pathway: A master regulator of liver metabolism, regeneration, and disease
Open accessAbstract
The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
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Hippo signaling is activated when the liver reaches normal size, suppressing YAP activity and reducing cell proliferation; YAP inhibition is one of the main mechanisms terminating liver regeneration.
“Hippo-YAP signaling pathway: Hippo signaling is activated when the liver reaches its normal size, suppressing YAP activity and thereby reducing cell proliferation. YAP inhibition is one of the main mechanisms terminating LR[96].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [96]
Termination of liver regeneration occurs via redundant and overlapping pathways-including TGF-β, Hippo-YAP, and Wnt/β-catenin, GPC3 activation-each contributing to halting hepatocyte proliferation and suppressing further liver regrowth.
“Rather than a single “off switch”, termination of liver regeneration occurs via redundant and overlapping pathways—including TGF-β, Hippo-YAP, and Wnt/β-catenin, GPC3 activation - each contributing to halting hepatocyte proliferation and suppressing further liver regrowth[96,100].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [96]
Cites
Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling
Yu, F.-X., Zhao, B., Panupinthu, N., Jewell, J. L., Lian, I., Wang, L. H., Zhao, J., Yuan, H., Tumaneng, K., Li, H., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.037 · Cited by 1,628 · see citing works
Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., & Taub, R. (1996) · Science · doi:10.1126/science.274.5291.1379 · Cited by 1,536 · see citing works
Michalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384 · see citing works
Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis
Diehl, A. M., & Day, C. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1503519 · Cited by 1,283 · see citing works
Yamada, Y., Kirillova, I., Peschon, J. J., & Fausto, N. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.4.1441 · Cited by 944 · see citing works
Hippo Pathway Activity Influences Liver Cell Fate
Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B. Z., & Camargo, F. D. (2014) · Cell · doi:10.1016/j.cell.2014.03.060 · Cited by 857 · see citing works
Basu, S., Totty, N. F., Irwin, M. S., Sudol, M., & Downward, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(02)00776-1 · Cited by 843 · see citing works
Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745 · see citing works
AMPK modulates Hippo pathway activity to regulate energy homeostasis
Wang, W., Xiao, Z.-D., Li, X., Aziz, K. E., Gan, B., Johnson, R. L., & Chen, J. (2015) · Nature Cell Biology · doi:10.1038/ncb3113 · Cited by 549 · see citing works
YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth
Low, B. C., Pan, C. Q., Shivashankar, G. V., Bershadsky, A., Sudol, M., & Sheetz, M. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.04.012 · Cited by 412 · see citing works
The Hippo pathway effector YAP controls mouse hepatic stellate cell activation
Mannaerts, I., Leite, S. B., Verhulst, S., Claerhout, S., Eysackers, N., Thoen, L. F. R., Hoorens, A., Reynaert, H., Halder, G., & van Grunsven, L. A. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.04.011 · Cited by 410 · see citing works
Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy
Akerman, P., Cote, P., Yang, S. Q., McClain, C., Nelson, S., Bagby, G. J., & Diehl, A. M. (1992) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1992.263.4.g579 · Cited by 401 · see citing works
Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice
Kim, I., Morimura, K., Shah, Y., Yang, Q., Ward, J. M., & Gonzalez, F. J. (2007) · Carcinogenesis · doi:10.1093/carcin/bgl249 · Cited by 357 · see citing works
Tschaharganeh, D. F., Chen, X., Latzko, P., Malz, M., Gaida, M. M., Felix, K., Ladu, S., Singer, S., Pinna, F., Gretz, N., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.02.009 · Cited by 326 · see citing works
DeRan, M., Yang, J., Shen, C.-H., Peters, E. C., Fitamant, J., Chan, P., Hsieh, M., Zhu, S., Asara, J. M., Zheng, B., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.036 · Cited by 316 · see citing works
A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway
Mohseni, M., Sun, J., Lau, A., Curtis, S., Goldsmith, J., Fox, V. L., Wei, C., Frazier, M., Samson, O., Wong, K.-K., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb2884 · Cited by 294 · see citing works
Liver zonation: Novel aspects of its regulation and its impact on homeostasis
Gebhardt, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i26.8491 · Cited by 275 · see citing works
Characterization of Hippo Pathway Components by Gene Inactivation
Plouffe, S. W., Meng, Z., Lin, K. C., Lin, B., Hong, A. W., Chun, J. V., & Guan, K.-L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.034 · Cited by 275 · see citing works
Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase
Ma, B., Chen, Y., Chen, L., Cheng, H., Mu, C., Li, J., Gao, R., Zhou, C., Cao, L., Liu, J., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3073 · Cited by 266 · see citing works
Disruption of Hepatic Adipogenesis Is Associated With Impaired Liver Regeneration in Mice
Shteyer, E., Liao, Y., Muglia, L. J., Hruz, P. W., & Rudnick, D. A. (2004) · Hepatology · doi:10.1002/hep.20462 · Cited by 234 · see citing works
The ???small for size??? liver syndrome
Tucker, O. N., & Heaton, N. (2005) · Current Opinion in Critical Care · doi:10.1097/01.ccx.0000157080.11117.45 · Cited by 180 · see citing works
Understanding Liver Regeneration
Gilgenkrantz, H., & Collin de l'Hortet, A. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2018.03.008 · Cited by 171 · see citing works
Differentiation of progenitors in the liver: a matter of local choice
Boulter, L., Lu, W.-Y., & Forbes, S. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66026 · Cited by 116 · see citing works
Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
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
Nguyen, H. B., Babcock, J. T., Wells, C. D., & Quilliam, L. A. (2013) · Oncogene · doi:10.1038/onc.2012.431 · Cited by 84 · see citing works
Suárez-Causado, A., Caballero-Díaz, D., Bertrán, E., Roncero, C., Addante, A., García-Álvaro, M., Fernández, M., Herrera, B., Porras, A., Fabregat, I., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.05.017 · Cited by 49 · see citing works
Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration
Meyer, K., Morales‐Navarrete, H., Seifert, S., Wilsch‐Braeuninger, M., Dahmen, U., Tanaka, E. M., Brusch, L., Kalaidzidis, Y., & Zerial, M. (2020) · Molecular Systems Biology · doi:10.15252/msb.20198985 · Cited by 39 · see citing works
YAP transcriptionally regulates ErbB2 to promote liver cell proliferation
Wang, E. Y., Cheng, J.-C., Thakur, A., Yi, Y., Tsai, S.-H., & Hoodless, P. A. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.07.004 · Cited by 24 · see citing works
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Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Liver regeneration after partial hepatectomy: Triggers and mechanisms
Korchilava, B., Khachidze, T., Megrelishvili, N., Svanadze, L., Kakabadze, M., Tsomaia, K., Jintcharadze, M., & Kordzaia, D. (2025) · World Journal of Hepatology · doi:10.4254/wjh.v17.i7.107378 · Cited by 21 · see citing works
- Authors
- Nguyen‐Lefebvre, A. T., Selzner, N., Wrana, J. L., & Bhat, M.
- Affiliations
- Lunenfeld-Tanenbaum Research Institute (CA)
- Toronto General Hospital (CA)
- Corresponding author
- Bhat, Mamatha
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2021-04-08
- Volume
- 35
- Issue
- 5
- Pages
- e21570-e21570
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W3152077788
- Cited by
- 58
- References
- 28
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 7
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The FASEB Journal (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Canadian Liver Foundation
- American Society of Transplantation
- Toronto General and Western Hospital Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Hippo signaling pathway, liver regeneration, hepatic metabolism, YAP, TAZ, partial hepatectomy, liver cancer, hepatocyte proliferation, liver disease
- MeSH terms
- Hippo Signaling Pathway, Animals, Humans, Liver, Liver Diseases, Liver Regeneration, Protein Serine-Threonine Kinases
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