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Liver portal fibrosis in dioxin receptor‐null mice that overexpress the latent transforming growth factor‐β‐binding protein‐1
Author(s) -
Corchero Javier,
MartínPartido Gervasio,
Dallas Sarah L.,
FernándezSalguero Pedro M.
Publication year - 2004
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.0959-9673.2004.00397.x
Subject(s) - biology , fibrosis , fibronectin , transforming growth factor beta , tgf beta receptor 2 , hepatic fibrosis , hepatic stellate cell , transforming growth factor , extracellular matrix , endocrinology , microbiology and biotechnology , medicine , receptor , growth factor , tgf alpha , biochemistry
Summary Mice lacking aryl hydrocarbon (dioxin) receptor (AhR) had variable degree of hepatic fibrosis and altered liver architecture. Transforming growth factor‐β (TGF‐β), a major profibrogenic molecule in the liver, is localized to the extracellular matrix by its association to the latent TGF‐β‐binding protein‐1 (LTBP‐1). Very recently, LTBP‐1 has been shown to be negatively regulated by the AhR. Embryonic fibroblasts from AhR‐null (AhR –/– ) mice overexpress LTBP‐1 and secrete four times more active TGF‐β than wild‐type fibroblasts. To test whether TGF‐β and LTBP‐1 overexpression colocalize within the fibrotic nodule of AhR –/– liver, we have characterized this hepatic portal fibrosis using collagen protein staining, immunohistochemistry and in situ hybridization. LTBP‐1 mRNA and protein were overexpressed in the fibrotic region and colocalized with other indicators of fibrosis such as collagen and fibronectin and the fibroblast marker proteins α‐actin and vimentin. TGF‐β protein also colocalized with fibrosis, although in contrast, TGF‐β mRNA expression, rather than restricted to the fibrotic compartment, was present throughout the hepatic parenchyma and exhibited similar levels in wild‐type and AhR –/– mice. These results suggest that LTBP‐1 targets TGF‐β to specific areas of the liver and that the AhR could be a negative regulator of liver fibrosis, possibly through the control of LTBP‐1 and TGF‐β activities.