Upstream eventUp Regulation, TGFbeta1 expression
Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Protein Alkylation leading to Liver Fibrosis||adjacent||High|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
Transforming growth factor beta 1 (TGF-β1) is the most potent fibrogenic factor for epatic stellate cells (HSCs). In response to TGF-β1, HSCs activate into myofibroblast-like cells, producing type I, III and IV collagen, proteoglycans like biglycan and decorin, glycoproteins like laminin, fibronectin, tenascin and glycosaminoglycan.  In the further course of events activated HSCs themselves express TGF-β1. TGF-β1 induces its own mRNA to sustain high levels in local sites of liver injury. The effects of TGF-β1 are mediated by intracellular signalling via Smad proteins. Smads 2 and 3 are stimulatory whereas Smad 7 is inhibitory. Smad1/5/8, MAP kinase and PI3 kinase are further signalling pathways in different cell types for TGF-β1 effects.  Concomitant with increased TGF-β production, HSC increase production of collagen. Connective tissue growth factor (CTGF) is a profibrogenic peptide induced by TGF-β, that stimulates the synthesis of collagen type I and fibronectin and may mediate some of the downstream effects of TGF-β. It is upregulated during activation of HSC, suggesting that its expression is another determinant of a fibrogenic response to TGF-β . During fibrogenesis, tissue and blood levels of active TGF-β are elevated and overexpression of TGF-β1 in transgenic mice can induce fibrosis. Additionally, experimental fibrosis can be inhibited by anti-TGF-β treatments with neutralizing antibodies or soluble TbRs (TGF-β receptors) .
Evidence Supporting this KER
It is difficult to get experimental evidence in vitro for TGF-β1-induced HSC activation because HSCs undergo spontaneous activation when cultured on plastic; nevertheless qualitative empirical evidence for temporal and incidence concordance for this KER exists. Czaja et al could prove that treatment of cultured hepatic cells with TGF-β1 increased type I pro-collagen mRNA levels 13-fold due to post-transcriptional gene regulation. Tan et al. discovered that short TGF-β1 pulses can exert long-lasting effects on fibroblasts. HSCs activated in culture do not fully reproduce the changes in gene expression observed in vivo. De Minicis et al investigated gene expression changes in 3 different models of HSC activation and compared gene expression profiles in culture (mice HSCs in co-culture with KCs) and in vivo and did not find a proper correlation.    
Uncertainties and Inconsistencies
There are no uncertainties that TGF-b1 activates HSCs.
Quantitative Understanding of the Linkage
no quantitative data
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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