Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1.
Mice lacking aryl hydrocarbon (dioxin) receptor (AhR) had variable degree of hepatic fibrosis and altered liver architecture. Transforming growth factor-beta (TGF-beta), a major profibrogenic molecule in the liver, is localized to the extracellular matrix by its association to the latent TGF-beta-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-beta than wild-type fibroblasts. To test whether TGF-beta 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 alpha-actin and vimentin. TGF-beta protein also colocalized with fibrosis, although in contrast, TGF-beta 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-beta 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-beta activities.
Corchero
Javier
J
Departamento de Bioquímicay Biología Molecular, Facultad de Ciencias Universidad de Extremadura, Badajoz, Spain.
Martín-Partido
Gervasio
G
Dallas
Sarah L
SL
Fernández-Salguero
Pedro M
PM
D000199:Actins / Q000032:analysis; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta / Q000032:analysis*; D053773:Transforming Growth Factor beta1; D014746:Vimentin / Q000032:analysis
D000199:Actins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014746:Vimentin