EXPRES: Exogenous and Endogenous Stress and Pathological Responses in Hepato-Gastrointestinal Diseases

EXPRES-entête

Team leaders: Anne Corlu (DR CNRS) & Bernard Fromenty (DR INSERM)

 

Gut and liver are key organs for the absorption and metabolism of nutrients, whose excess can lead to obesity and nonalcoholic fatty liver disease (NAFLD). In addition, the liver can be exposed to a large array of toxic xenobiotics and to inflammatory mediators released by the gastrointestinal (GI) tract. Although these tissues are able to set up mechanisms of defense and repair in order to avoid the deleterious consequences of these stressors, the adaptive responses can be impaired in some individuals, thus favouring the occurrence of diseases such as inflammatory bowel diseases, colorectal cancer, steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.

In this context, the objectives of our team are to improve the understanding of cellular and molecular mechanisms involved in:

i) cell and tissue damage induced by different endogenous and exogenous stressors including infections and sepsis, lipid overload, surgery, hypoxia and xenobiotics,

ii) cell defense and tissue repair aiming at limiting the injury in liver and GI tract induced by these different stresses and,

iii) the occurrence of different pathological responses (e.g. inflammation, fibrosis and carcinogenesis) that can be secondary to a failure of cell defenses and tissue repair. When appropriate, we will also study the impact of obesity and/or NAFLD on the response to stress and on disease progression.

These different objectives are included in three major research themes:

1) hepatotoxicity of xenobiotics in normal and fatty liver;

2) response to inflammatory stress and pathophysiological consequences;

3) cell plasticity in liver regeneration, fibrosis and cancer.

Notably, novel experimental approaches are bridged with clinical investigations within each major theme. Moreover, these three themes are scientifically intertwined, in particular regarding cell defence, tissue repair, inflammation and mitochondrial dysfunction. We expect that our project will provide new paradigms that will help to understand the pathophysiology of several important hepato-gastrointestinal diseases and to find efficient and safe drugs for their treatment. We also hope that our investigations will allow to find new strategies in order to stimulate liver regeneration without inducing adverse events that could favour fibrosis or carcinogenesis.

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This project gathers researchers and clinicians with expertise in toxicology, mechanisms of cellular defense and detoxication, proliferation and response to inflammation and matrix remodeling. Notably, many members of our team are involved in teaching and training or in several European and national projects or have international collaborations with different Universities in Spain, Germany, UK, Japan, Brazil and the US as well as national collaborations with pharmaceutical companies or biotechs (Sanofi-Aventis, Servier, Roche, Mitologics, HCS-Pharma…). Several clinicians are also involved in different patient associations.

Major publications

  1. Nesseler N, Launey Y, Aninat C, White J, Corlu A, Mallédant Y, Seguin P. Liver dysfunction is associated with long term mortality in septic shock. Am. J. Respir. Crit. Care Med. 2015 (in press). [IF 2014: 12.99]
  1. Gicquel T, Robert S, Loyer P, Victoni T, Bodin A, Ribault C, Gleonnec F, Couillin I, Boichot E, Lagente V. IL-1β production is dependent of the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J. 2015 (in press). [IF 2014: 5.04]
  1. Bouguen G, Langlois A, Djouina M, Branche J, Koriche D, Dewaeles E, Mongy A, Auwerx J, Colombel JF, Desreumaux P, Dubuquoy L, Bertin B. Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis. Gut 2015; 64: 901-10. [IF 2014: 14.66]
  1. Dubois-Pot-Schneider H, Fekir K, Coulouarn C, Glaise D, Aninat C, Jarnouen K, Le Guével R, Kubo T, Ishida S, Morel F, Corlu A. Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells. Hepatology 2014; 60: 2077-90. [IF 2014: 11.05]
  1. Anthérieu S, Bachour-El Azzi P, Dumont J, Abdel-Razzak Z, Guguen-Guillouzo C, Fromenty B, Robin MA, Guillouzo A. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells. Hepatology 2013; 57: 1518-29. [IF 2014: 11.05]

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