Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms
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BACKGROUND/AIMS: During development of liver fibrosis, an important source of myofibroblasts is hepatocytes, which differentiate into myofibroblasts by epithelial to mesenchymal transition (EMT). In epithelial tumours and kidney fibrosis, hypoxia, through activation of hypoxia-inducible factors (HIFs), is an important stimulus of EMT. Our recent studies demonstrated that HIF-1alpha is important for the development of liver fibrosis. Accordingly, the hypothesis was tested that hypoxia stimulates hepatocyte EMT by a HIF-dependent mechanism. METHODS: Primary mouse hepatocytes were exposed to room air or 1% oxygen and EMT evaluated. In addition, bile duct ligations (BDLs) were performed in control and HIF-1alpha-deficient mice and EMT quantified. RESULTS: Exposure of hepatocytes to 1% oxygen increased expression of alpha-smooth muscle actin, vimentin, Snail and fibroblast-specific protein-1 (FSP-1). Levels of E-cadherin and zona occludens-1 were decreased. Upregulation of FSP-1 and Snail by hypoxia was completely prevented in HIF-1beta-deficient hepatocytes and by pretreatment with SB431542, a transforming growth factor-beta (TGF-beta) receptor inhibitor. HIFs promoted TGF-beta-dependent EMT by stimulating activation of latent TGF-beta1. To determine whether HIF-1alpha contributes to EMT in the liver during the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. FSP-1 was increased to a greater extent in the livers of control mice when compared with HIF-1alpha-deficient mice. CONCLUSIONS: Results from these studies demonstrate that hypoxia stimulates hepatocyte EMT by a HIF and TGF-beta-dependent mechanism. Furthermore, these studies suggest that HIF-1alpha is important for EMT in the liver during the development of fibrosis.
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The HIF pathway indirectly promotes EMT through Notch, TGF-β, integrin-linked kinase, certain tyrosine kinase receptors, Wnt, and Hedgehog.
“The HIF pathway also indirectly promotes EMT through a number of cell signaling pathways, including Notch (74, 75), TGF-β (76), integrin-linked kinase (77), certain tyrosine kinase receptors (48), Wnt (73), and Hedgehog (78, 79).”
From Hypoxic control of metastasis (2016) · cites this paper as [76]
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- Authors
- Copple, B. L.
- Affiliations
- University of Kansas Medical Center (US)
- Corresponding author
- Copple, Bryan L.
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2010-05
- Volume
- 30
- Issue
- 5
- Pages
- 669-682
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- PMC
- PMC3111074
- OpenAlex
- W2039775393
- Cited by
- 164
- References
- 30
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 16 · 2021: 16 · 2020: 13 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 16 · 2014: 11 · 2013: 16 · 2012: 8
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Liver International (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (DK073566, R01DK073566)
- National Center for Research Resources (P20RR021940, P20RR016475)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hypoxia, epithelial-mesenchymal transition, hepatocytes, hypoxia-inducible factor-1α, TGF-beta, liver fibrosis, myofibroblast differentiation, bile duct ligation, alpha-smooth muscle actin, snails, S100A4, TGF-β receptor inhibition
- MeSH terms
- S100 Calcium-Binding Protein A4, Actins, Animals, Calcium-Binding Proteins, Epithelial Cells, Membrane Proteins, Mesoderm, Mice, Inbred C57BL, S100 Proteins, Phosphoproteins, Cell Hypoxia, Cadherins, Hepatocytes, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Keratin-19, Transforming Growth Factor beta1, Zonula Occludens-1 Protein
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