We have located links that may give you full text access.
JOURNAL ARTICLE
RESEARCH SUPPORT, N.I.H., EXTRAMURAL
Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms.
Liver International : Official Journal of the International Association for the Study of the Liver 2010 May
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.
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.
Full text links
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app