Upstream eventUp Regulation, TGFbeta1 expression
Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Protein Alkylation leading to Liver Fibrosis||directly leads to||Strong|
|Rattus norvegicus||Rattus norvegicus||Strong||NCBI|
Life Stage Applicability
How Does This Key Event Relationship Work
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) .
Weight of Evidence
Empirical Support for Linkage
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 or Inconsistencies
There are no uncertainties that TGF-b1 activates HSCs.
Quantitative Understanding of the Linkage
no quantitative data
Evidence Supporting Taxonomic Applicability
- Kisseleva, T. and Brenner, D.A. (2007), Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis, Journal of Gastroenterology and Hepatology, vol. 22, Suppl. 1; pp. S73–S78.
- Parsons, C.J., M.Takashima and R.A. Rippe (2007), Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol, vol. 22, Suppl.1, pp. S79-S84.
- Williams, E.J. et al. (2000), Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells, J Hepatol, vol. 32, no. 5, pp. 754-761.
- Qi Z et al. (1999), Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat, Proc Natl Acad Sci USA, vol. 96, no. 5, pp. 2345-2349.
- Gressner , A.M. et al. (2002), Roles of TGF-β in hepatic fibrosis. Front Biosci, vol. 7, pp. 793-807.
- Kolios, G., V. Valatas and E. Kouroumalis (2006), Role of Kupffer cells in the pathogenesis of liver disease, World J.Gastroenterol, vol. 12, no. 46, pp. 7413-7420.
- Bataller, R. and D.A. Brenner (2005), Liver Fibrosis, J.Clin. Invest, vol. 115, no. 2, pp. 209-218.
- Guo, J. and S. L. Friedman (2007), Hepatic fibrogenesis, Semin Liver Dis, vol. 27, no. 4, pp. 413-426.
- Brenner, D.A. (2009), Molecular Pathogenesis of Liver Fibrosis, Trans Am Clin Climatol Assoc, vol. 120, pp. 361–368.
- Kaimori, A. et al. (2007), Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro, J Biol Chem, vol. 282, no. 30, pp. 22089-22101.
- Kershenobich Stalnikowitz, D. and A.B. Weisssbrod (2003), Liver Fibrosis and Inflammation. A Review, Annals of Hepatology, vol. 2, no. 4, pp.159-163.
- Li, Jing-Ting et al. (2008), Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies, J Gastroenterol, vol. 43, no. 6, pp. 419–428.
- Matsuoka, M. and H. Tsukamoto, (1990), Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis, Hepatology, vol. 11, no. 4, pp. 599-605.
- Kisseleva T and Brenner DA, (2008), Mechanisms of Fibrogenesis, Exp Biol Med, vol. 233, no. 2, pp. 109-122.
- Poli, G. (2000), Pathogenesis of liver fibrosis: role of oxidative stress, Mol Aspects Med, vol. 21, no. 3, pp. 49 – 98.
- Friedman, S.L. (2008), Mechanisms of Hepatic Fibrogenesis, Gastroenterology, vol. 134, no. 6, pp. 1655–1669.
- Liu, Xingjun et al. (2006), Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis. Liver Int, vol.26, no.1, pp. 8-22.
- Czaja, M.J. et al. (1989), In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis, J Cell Biol, vol. 108, no. 6, pp. 2477-2482.
- Tan, A.B. et al. (2013), Cellular re- and de-programming by microenvironmental memory: why short TGF-β1 pulses can have long effects, Fibrogenesis Tissue Repair, vol. 6, no. 1, p. 12.
- Yin, C. et al. (2013), Hepatic stellate cells in liver development, regeneration, and cancer, J Clin Invest, vol. 123, no. 5, pp. 1902–1910.
- De Minicis, S. et al. (2007), Gene expression profiles during hepatic stellate cell activation in culture and in vivo, Gastroenterology, vol. 132, no. 5, pp. 1937-1946.
- Dooley, S. et al. (2000), Modulation of transforming growth factor b response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts,Hepatology, vol. 31, no. 5, pp. 1094-1106.