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Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery
Open accessAbstract
The hepatoprotective effect of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) has been well documented. However, reports on the role of IL-6/STAT3 in liver regeneration are conflicting probably due to the fact that the model of Stat3 knockout mice were complicated with obesity and fatty liver, which may cause some secondary effects on liver regeneration. To study the direct role of STAT3 and to circumvent the problems of obesity and fatty liver in liver regeneration, we generated conditional STAT3 knockout in the liver (L-Stat3(-/-)) using a transthyretin-driven Cre-lox method. The L-Stat3(-/-) mice were born with the expected Mendelian frequency and showed no obesity or other obvious phenotype. After partial hepatectomy, mortality in the L-Stat3(-/-) mice was significantly higher than the littermate Stat3(f/+) controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3(-/-) mice slightly decreased as compared with Stat3(f/+) mice at 40 h after partial hepatectomy, whereas similar hepatocyte DNA synthesis was found at other time points and liver mass could be completely recovered in the L-Stat3(-/-) mice. In another model of liver regeneration induced by subcutaneous injection of carbon tetrachloride (CCl(4)), hepatocyte DNA synthesis in the CCl(4)-treated L-Stat3(-/-) mice also decreased as compared with Stat3(f/+) mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl(4)-treated L-Stat3(-/-) mice compared to wild-type mice. In conclusion, STAT3 is required for survival in the acute stage after 70% hepatectomy and plays a role in inflammatory reaction after hepatocyte necrosis. However, the hepatocytic STAT3 may have limited role in liver mass recovery although DNA synthesis may be impaired.
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“Successful LR depends on an intact TNF-NFκB-IL-6-STAT3 pathway.”
From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [29]
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“Insulin resistance; impaired liver regeneration”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Moh et al., 2007
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“By contrast, the effect of liver-specific Stat3 deletion was relatively modest (71, 72)”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [72]
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Metadata
- Authors
- Moh, A., Iwamoto, Y., Chai, G.-X., Zhang, S. S.-M., Kano, A., Yang, D. D., Zhang, W., Wang, J., Jacoby, J. J., Gao, B., Flavell, R. A., & Fu, X.-Y.
- Affiliations
- Indiana University School of Medicine (US)
- Yale University (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Fu, Xin-Yuan
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 87
- Issue
- 10
- Pages
- 1018-1028
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2090563155
- Cited by
- 147
- References
- 39
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 5 · 2023: 14 · 2022: 9 · 2021: 13 · 2020: 13 · 2019: 8 · 2018: 11 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 5 · 2013: 9 · 2012: 7
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Yale University
- National Institutes of Health (5r01ar044906-05, DK34989)
- U.S. Army
- National Institute of Allergy and Infectious Diseases (R01AI34522, R01AI034522)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-34989, P30DK034989)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR-44906)
- Yale Liver Center (DK34989)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- STAT3, liver regeneration, interleukin-6, partial hepatectomy, carbon tetrachloride, hepatocyte DNA synthesis, hepatocyte viability, liver inflammation, neutrophil infiltration, monocyte infiltration, liver necrosis
- MeSH terms
- Animals, Carbon Tetrachloride, Digestive System, Disease Models, Animal, DNA, Hepatectomy, Inflammation, Liver, Liver Regeneration, Gene Deletion, Mice, Knockout, Integrases, Hepatocytes, Hepatic Insufficiency, STAT1 Transcription Factor, STAT3 Transcription Factor, Mice
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