Exogenous and endogenous stress, plasticity of responses and diseases

Team leaders :

Anne Corlu & Bernard Fromenty

Gut and liver are key organs for the absorption and metabolism of nutrients such as carbohydrates and lipids, which in excess can induce obesity and associated diseases such as metabolic dysfunction-associated nonalcoholic fatty liver disease (MAFLD). In addition, liver is exposed to many toxic xenobiotics as well as to pro-inflammatory mediators released from tissues including the gastrointestinal tract. Although these tissues have defense and repair mechanisms in order to curb the harmful consequences of these stressors, the adaptive responses are altered in certain individuals, thus promoting the occurrence of various pathologies such as chronic inflammatory bowel disease (IBD), MAFLD (including extensive fibrosis and cirrhosis) and hepatocellular carcinoma (HCC), or aggravation of sepsis. Consequently, the plasticity of responses to different types of stress leads in some cases to the development of severe pathologies. The impact of obesity and MAFLD on impaired stress response is also investigated.

In this pathophysiological context, our investigations are developed around two main axes:

Theme 1: Biological and toxic effects of xenobiotics and lipids. This theme is divided into 3 sub-themes: a) Liver toxicity of xenobiotics including certain drugs and environmental toxins such as endocrine disruptors; b) Deleterious and beneficial effects of dietary and endogenous fatty acids; c) Impacts of MAFLD and insulin resistance on some cytochromes P450 (CYPs), in particular CYP2E1.

Theme 2: Tissue remodeling and metabolic reprogramming. This theme is divided into 3 sub-topics: a) Inflammation and epithelial healing; b) Inflammatory and metabolic response to stress including hypoxia and infections; c) Microenvironment and phenotypic plasticity in tumor progression and drug resistance in the context of HCC.

These two themes share common keywords such as “mitochondria”, “lipids”, “inflammation” and “oxidative stress”. For some research projects, the experimental approaches are supplemented by clinical investigations supervised by clinicians from the team. Our goal is to provide new paradigms that will allow a better understanding of the pathophysiology of different severe hepato-gastrointestinal diseases and to discover effective and non-toxic therapeutic approaches for their treatment. We also hope that our investigations will help to find new strategies to stimulate intestinal healing or hepatic regeneration without inducing deleterious effects that could promote fibrosis or carcinogenesis.

Recent publications :

  1. Allard J., Bucher S., Massart J., Ferron P.J., Le Guillou D., Loyant R., Daniel Y., Launay Y., Buron N., Begriche K., Borgne-Sanchez A., Fromenty B. (2020) Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity. Cell Biol Toxicol, vol n°, p., DOI: https://doi.org/10.1007/s10565-020-09537-1.
  2. Bouguen G., Huguet A., Amiot A., Viennot S., Cholet F., Nachury M., Flamant M., Reimund J.M., Desfourneaux V., Boureille A., Siproudhis L., Getaid. (2020) Efficacy and Safety of Tumor Necrosis Factor Antagonists in Treatment of Internal Fistulizing Crohn’s Disease. Clin Gastroenterol Hepatol, vol 18, n°3, 628-636 p., DOI: https://doi.org/10.1016/j.cgh.2019.05.027.
  3. Guillocheau E, Legrand P, Rioux V (2020) Trans-palmitoleic acid (trans-9-C16:1, or trans-C16:1 n-7): Nutritional impacts, metabolism, origin, compositional data, analytical methods and chemical synthesis. A review. Biochimie, Vol 169, 144-160 p., DOI: https://doi.org/ 10.1016/j.biochi.2019.12.004.
  4. Nesseler N., Rached A., Ross J.T., Launey Y., Vigneau C., Bensalah K., Beloeil H., Mallédant Y., Garlantezec R., Seguin P. (2020) Association between perioperative normal saline and delayed graft function in deceased-donor kidney transplantation: a retrospective observational study. Can J Anaesth, vol 67, n°4, 421-429 p., DOI: https://doi.org/10.1007/s12630-020-01577-9.
  5. Bouvet R., Cauchois A., Baert A., Fromenty B., Morel I., Turlin B., Gicquel T. (2020) Fatal acetaminophen poisoning with hepatic microvesicular steatosis in a child after repeated administration of therapeutic doses. Forensic Sci Int, vol 310, n°, p., DOI: https://doi.org/10.1016/j.forsciint.2020.110258.
  6. Fekir K., Dubois-Pot-Schneider H., Désert R., Daniel Y., Glaise D., Rauch C., Morel F., Fromenty B., Musso O., Cabillic F., Corlu A. (2019) Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance. Cancer Res, vol 79, n°8, 1869-1883 p., DOI: https://doi.org/10.1158/0008-5472.CAN-18-2110.
  7. Le Daré B., Lagente V., Gicquel T. (2019) Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects. Drug Metab Rev, vol 51, n°4, 545-561 p., DOI: https://doi.org/10.1080/03602532.2019.1679169.
  8. Musso O., Beraza N. (2019) Hepatocellular carcinomas: evolution to sorafenib resistance through hepatic leukaemia factor. Gut, vol 68, n°10, 1728-1730 p., DOI: https://doi.org/10.1136/gutjnl-2019-318999.
  9. Nesseler N., Martin-Chouly C., Perrichet H., Ross J.T., Rousseau C., Sinha P., Isslame S., Masseret E., Mallédant Y., Launey Y., Seguin P. (2019) Low interleukin-10 release after ex vivo stimulation of whole blood is associated with persistent organ dysfunction in sepsis: A prospective observational study. Anaesth Crit Care Pain Med, vol 38, n°5, 485-491 p., DOI: https://doi.org/10.1016/j.accpm.2019.01.009.
  10. Dornas W., Glaise D., Bodin A., Sharanek A., Burban A., Le Guillou D., Robert S., Dutertre S., Aninat C., Corlu A., Lagente V. (2018) Endotoxin regulates matrix genes increasing reactive oxygen species generation by intercellular communication between palmitate-treated hepatocyte and stellate cell. J Cell Physiol, vol 234, n°1, 122-133 p., DOI: https://doi.org/10.1002/jcp.27175.
  11. Désert R., Nieto N., Musso O. (2018) Dimensions of hepatocellular carcinoma phenotypic diversity. World J Gastroenterol, vol 24, n°40, 4536-4547 p., DOI: https://doi.org/10.3748/wjg.v24.i40.4536.
  12. Burban A., Sharanek A., Guguen-Guillouzo C., Guillouzo A. (2018) Endoplasmic reticulum stress precedes oxidative stress in antibiotic-induced cholestasis and cytotoxicity in human hepatocytes. Free Radic Biol Med, vol 115, n°, 166-178 p., DOI: https://doi.org/10.1016/j.freeradbiomed.2017.11.017.

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