Transforming Growth Factor-β (TGF-β)-mediated Connective Tissue Growth Factor (CTGF) Expression in Hepatic Stellate Cells Requires Stat3 Signaling Activation
Open accessAbstract
In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified. In this study, we report involvement of Stat3 activation in modulating CTGF production upon TGF-β challenge in activated HSCs. Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like kinase 5) downstream signaling molecule to mediate CTGF expression. This process requires de novo gene transcription and is additionally modulated by MEK1/2, JNK, and PI3K pathways. Cell-specific knockdown of Smad3 partially decreases CTGF production, whereas it has no significant influence on Stat3 activation. The total CTGF production induced by TGF-β in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways.
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Previous studies detected elevated STAT3 phosphorylation in all rodent models with liver injury and fibrosis and in samples of patients with fibrosis and cirrhosis.
“Previous studies detected elevated STAT3 phosphorylation in all rodent models with liver injury and fibrosis and in the samples of patients with fibrosis and cirrhosis [46, 47].”
From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [46]
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- Authors
- Liu, Y., Liu, H., Meyer, C., Li, J., Nadalin, S., Königsrainer, A., Weng, H., Dooley, S., & ten Dijke, P.
- Affiliations
- Heidelberg University (DE)
- Shanghai Jiao Tong University (CN)
- Universitätsklinikum Tübingen (DE)
- Corresponding author
- Dooley, Steven
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 288
- Issue
- 42
- Pages
- 30708-30719
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3798541
- OpenAlex
- W2050345976
- Cited by
- 181
- References
- 0
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 12 · 2023: 8 · 2022: 13 · 2021: 15 · 2020: 16 · 2019: 18 · 2018: 20 · 2017: 17 · 2016: 16 · 2015: 19 · 2014: 13 · 2013: 1
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- connective tissue growth factor, hepatic stellate cells, TGF-beta signaling, STAT3, Smad3, liver fibrosis, extracellular matrix synthesis, JAK1, ALK5, MEK1/2, JNK, phosphatidylinositol 3-kinase, gene transcription
- MeSH terms
- Cell Line, Transformed, Extracellular Matrix, Female, Gene Expression Regulation, Humans, Liver Cirrhosis, Male, Transforming Growth Factor beta, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, STAT3 Transcription Factor, Smad3 Protein, Janus Kinase 1, Hepatic Stellate Cells, Connective Tissue Growth Factor
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