Topic 1 : LIVER FIBROSIS / AUTOPHAGY

Topics - overview

Title

Project leader

Transcriptional regulation of hepatic stellate cell activation in pathological conditions Leo van Grunsven PhD

Postdoc project

Inge Mannaerts
PhD

Role of specific HDACs during hepatic stellate cell activation
Interplay between epigenetic modification mechanisms and microRNAs
Integration of stress pathways during the onset of hepatic stellate cell activation

PhD projects

Leslie Stradiot

Modulation of liver fibrosis by liposome-mediated selective targeting of hepatic stellate cells (2013-2016)

Joeri Lambrecht

Staging of liver fibrosis by hepatic stellate cell specific biomarkers (2014-2020)

Lien Thoen

FINALIZED IN 2015: The Role Of Stress Pathways During Hepatic Stellate Cell Activation

Current Funding

 

Transcriptional regulation of hepatic stellate cell activation in pathological conditions

Worldwide, chronic liver disease is a major cause of mortality and morbidity. Cirrhosis of the liver results from chronic pro-inflammatory insults resulting from viral infections (e.g.Hepatitis C) to autoimmune and toxicity (e.g. alcoholic liver disease or the metabolic syndrome), that lead to progressive fibrosis of the liver as part of the body's wound healing and tissue remodeling mechanisms. Central obesity is an acknowledged causative factor for metabolic syndrome which is a cluster of metabolically related abnormalities i.e. visceral adiposity, dyslipidaemia, hyperglycaemia and hypertension that predict an increased risk for cardio-vascular diseases, type II diabetes mellitus, non-alcoholic steatohepatitis and certain cancers (1,2). It is well established that in hepatocytes, the insulin resistant state is brought about by -a combination of- hyper-glycaemia and hyper-insulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. The influence of many of these pathological alterations on sinusoidal cells and more in particular on the activation of hepatic stellate cells is largely unknown (3). Fibrotic diseases are characterized by scar formation due to abundant production and deposition of extracellular matrix proteins. The identification of stellate cells as the primary source of extracellular matrix proteins was a considerable step forward towards the understanding of the mechanism of liver fibrosis and towards the development of new therapeutic strategies. Chronic liver injuries e.g. viral infections, metabolic diseases, genetic disorders or alcohol abuse, lead to transition of the stellate cells to myofibroblast-like cells (4). These activated cells are fast proliferating cells that lose their capacity to store vitamin A and produce excessive amounts of extra-cellular matrix proteins thereby causing scar formation (5,6). This activation is, in vitro and in vivo, accompanied by strong changes in gene expression (7-9).
The aim of this topic is to understand the gene expression changes observed during stellate cell activation in vivo and in vitro (tissue-culture induced stellate cell activation, a widely accepted model for in vivo hepatic stellate cell activation). The characterization of transcriptional repressor complexes involved in the activation process is a recent topic that has been prompted by an older study carried out by the CYTO lab on the effect of Histon Deacetylase inhibitors on stellate cell activation (10,11). In addition we try to mimic some of the aspects of the metabolic syndrome e.g. high concentrations of insulin, leptin and advanced glycation end products in the culture medium to investigate their influence on the transdifferentiation potential of the freshly isolated hepatic stellate cells. Using these approaches we gain insight into the mechanisms of stellate cell activation that can occur due to the chronic pro-inflammatory insults described above.

References
1.Despres, J.-P. & Lemieux, I. Nature 444, 881-887 (2006) 2.Anderson, P. J. et al. Int J Obes Relat Metab Disord 25, 1782-8 (2001) 3.Leclercq, I. A, et al. Journal of Hepatology 47, 142-156 (2007) 4.Friedman, S. L. & Bansal, M. B. Hepatology 43, S82-8 (2006) 5.Blomhoff, R. & Wake, K. Faseb J 5, 271-7 (1991) 6.Kent, G. et al. Proc Natl Acad Sci U S A 73, 3719-22 (1976) 7.De Minicis, S. et al. Gastroenterology 132, 1937-1946 (2007) 8.Jiang, F., Parsons, C. J. & Stefanovic, B. Journal of Hepatology 45, 401-409 (2006) 9.Takahara, Y. et al. World J Gastroenterol 12, 6473-99 (2006) 10.Rombouts, K. et al. Journal of Hepatology 37, 788-796 (2002) 11.Niki, T. et al. Hepatology 29, 858-67 (1999)

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