Upstream eventCell injury/death
Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Protein Alkylation leading to Liver Fibrosis||non-adjacent||High|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
Damaged hepatocytes can lead to activation of hepatic stellate cells (HSCs) through the release of ROS, cytokines and chemokines. Engulfment of apoptotic bodies from hepatocytes results in HSC activation and induces NOX (NADPH oxidases) expression in HSCs. DNA from apoptotic hepatocytes induces toll-like receptor 9 (TLR9)-dependent changes of HSCs that are consistent with late stages of HSC differentiation (activation), with up-regulation of collagen production and inhibition of platelet derived growth factor (PDGF)-mediated chemotaxis to retain HSCs at sites of cellular apoptosis. The release of latent TGF-beta complex into the micro-environment by damaged hepatocytes is likely to be one of the first signals for adjacent HSCs leading to their activation.
Damaged hepatocytes also influence liver sinusoidal endothelial cell (LSECs), which make an integral part of the hepatic reticulo-endothelial system and have a role in HSC activation. LSECs are morphologically identified by their fenestrations, which are transcytoplasmic canals arranged in sieve plates. In healthy liver, hepatocytes and HSCs maintain this phenotype of LSECs through release of vascular endothelial growth factor (VEGF). Differentiated (i.e. fenestrated) LSECs prevent HSC activation and promote reversal of activated HSC to quiescence, but LSEC lose this effect when they are de-differentiated due to liver injury. Preclinical studies have demonstrated that LSECs undergo defenestration as an early event that not only precedes liver fibrosis, but may also be permissive for it. Changes in LSEC differentiation might be an integral part of the development of fibrosis. Furthermore, in fibrosis LSECs become highly pro-inflammatory and secrete an array of cytokines and chemokines     
This relationship is classified as indirect as HSCs activation is partly mediated by TGF-β1 and LSECs.
Evidence Supporting this KER
There is temporal concordance as HSC activation follows hepatic injury and there is experimental evidence for this KER. Canbay et al. could show that Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. Markers of HSC activation were significantly reduced when apoptosis was prevented in Fas-deficient bile duct ligated mice. These findings (reduction of inflammation, markers of HSC activation, and collagen I expression) could be repeated by pharmacological inhibition of liver cell apoptosis using a pan-caspase inhibitor. Coulouarn et al found in a co-culture model that hepatocyte - HSC crosstalk engenders a permissive inflammatory microenvironment.   
Uncertainties and Inconsistencies
There are no inconsistencies
Quantitative Understanding of the Linkage
There are no quantitative data
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Roth, S., K. Michel and A.M. Gressner (1998), (Latent) transforming growth factor beta in liver parenchymal cells, its injury-dependent release, and paracrine effects on rat HSCs, Hepatology, vol. 27, no. 4, pp. 1003-1012.
- Gressner , A.M. et al. (2002), Roles of TGF-β in hepatic fibrosis. Front Biosci, vol. 7, pp. 793-807.
- Malhi, H. et al. (2010), Hepatocyte death: a clear and present danger, Physiol Rev, vol. 90, no. 3, pp. 1165-1194.
- Canbay, A., S.L. Friedman and G.J. Gores (2004), Apoptosis: the nexus of liver injury and fibrosis, Hepatology, vol. 39, no. 2, pp. 273-278.
- Orrenius, S., P. Nicotera and B. Zhivotovsky (2011), Cell death mechanisms and their implications in toxicology, Toxicol. Sci, vol. 119, no. 1, pp. 3-19.
- 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.
- Kisseleva T and Brenner DA, (2008), Mechanisms of Fibrogenesis, Exp Biol Med, vol. 233, no. 2, pp. 109-122.
- 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.
- Friedman, S.L. (2008), Mechanisms of Hepatic Fibrogenesis, Gastroenterology, vol. 134, no. 6, pp. 1655–1669.
- Lee, U.E. and S.L. Friedman (2011), Mechanisms of Hepatic Fibrogenesis, Best Pract Res Clin Gastroenterol, vol. 25, no. 2, pp. 195-206.
- DeLeve, L.D. (2013), Liver sinusoidal endothelial cells and liver regeneration, J Clin Invest, vol. 123, no. 5, pp. 1861–1866.
- Xie, G. et al. (2012), Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats, Gastroenterology, vol. 142, no. 4, pp. 918–927.
- Xie, G. et al. (2013), Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation, Gut, vol. 62, no. 2, pp. 299–309.
- Ding, B.S. et al. (2014), Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis, Nature, vol. 505, no. 7481, pp. 97–102.
- Connolly, M.K. et al. (2010), In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity, J Immunol, vol. 185, no. 4, pp. 2200-2208.
- Canbay, A. et al. (2002), Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis, Gastroenterology, vol. 123, no. 4, pp. 1323-1330.
- Canbay, A. et al. (2004), The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse, J Pharmacol Exp Ther, vol. 308, no. 3, pp. 1191-1196.
- Coulouarn, C. et al. (2012), Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory micro-environment that drives progression in hepatocellular carcinoma, Cancer Res, vol. 72, no. 10, pp. 2533–2542.