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Hypoxia Stimulates Hepatocyte Epithelial to Mesenchymal Transition
Author(s) -
Copple Bryan L,
Sullivan Bradley,
Bai Shan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.236.9
Subject(s) - epithelial–mesenchymal transition , downregulation and upregulation , hepatocyte , hypoxia (environmental) , hepatocyte growth factor , follistatin , in vivo , biology , chemistry , transforming growth factor , endocrinology , medicine , microbiology and biotechnology , in vitro , receptor , biochemistry , organic chemistry , oxygen , gene
Studies have shown that hepatocytes differentiate into myofibroblasts during fibrosis by a process called epithelial to mesenchymal transition (EMT). In kidney fibrosis, hypoxia, through activation of the transcription factor hypoxia‐inducible factors‐1α (HIF‐1α) is an important stimulus of EMT. Accordingly, we tested the hypothesis that hypoxia stimulates hepatocyte EMT by a HIF‐dependent mechanism. Exposure of primary mouse hepatocytes to hypoxia increased fibroblast‐specific protein‐1 (FSP‐1) and SNAIL, and decreased E‐cadherin and zona occludins‐1 consistent with EMT. Upregulation of FSP‐1 and SNAIL was prevented in hepatocytes isolated from HIF‐1β‐deficient mice. In addition, upregulation of FSP‐1 and SNAIL was partially prevented by pretreatment with the activin inhibitor, follistatin, and by pretreatment with a transforming growth factor‐β1‐neutralizing antibody. This suggested that activins and TGF‐β1 were required for hypoxia‐induced EMT. Consistent with these in vitro results, mRNA and protein levels of FSP‐1 were increased to a greater extent in the livers of wild‐type mice after bile duct ligation when compared to HIF‐1α‐deficient mice. Results from these studies demonstrate that hypoxia stimulates hepatocyte EMT in vitro and in vivo by a HIF‐dependent mechanism. Supported by NIH grant DK073566.