API

Relationship: 303

Title

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Up Regulation, TGFbeta1 expression leads to Accumulation, Collagen

Upstream event

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Up Regulation, TGFbeta1 expression

Downstream event

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Accumulation, Collagen

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI

Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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TGF-β1 does not only activate HSCs, but also stimulate ECM synthesis and suppresses ECM degradation. It stimulates collagen transcription in stellate cells and connective tissue growth factor (CTGF) in hepatocytes and induces the expression of TIMP-1, an inhibitor of the collagen cleaving enzymes MMP-8 and MMP-13. TGF-β1 increases the α1(I) collagen mRNA half-life, mediated by increasing stability of α1(I) collagen mRNA through MAPK but not Smad signaling. TGF-β1 further recruits inflammatory cells, portal fibroblasts and circulating myofibroblasts to injured liver and triggers apoptosis of hepatocytes. In mature (i.e. adult) hepatocytes, TGF-β1 is responsible for inhibition of cell proliferation and induction of apoptosis. Interestingly, TGF-β1 is the most established mediator and regulator of epithelial-mesenchymal-transition (EMT) hich further contributes to te production of extracellular matrix. It has been shown that TGF-β1 mediates EMT by inducing snail-1 transcription factor and tyrosine phosphorylation of Smad2/3 with subsequent recruitment of Smad4.

Weight of Evidence

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Biological Plausibility

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Empirical Support for Linkage

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Uncertainties or Inconsistencies

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Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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References

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Kolios et al., World J Gastroenterol 2006 December 14; 12(46): 7413-7420

Bataller and Brenner 2005, J.Clin. Invest. 11:209-218

Guo and Friedman 2007.SeminLiver Dis 27:413-426

Brenner 2009, Transactions of the America Clinical and Climatological Association, Vol 120

Li GT, J Gastroenterol 2008; 43:419–428

Kaimori A., 2007, J. of Biological Chemistry Vol 282. Nr30

Gressner et al. 2002, Front Biosci. Apr 1;7:d793-807

Stalnikowitz 2003, Annals of Hepatology, 2(4) 159-163