Fibro-inflammatory liver diseases of metabolic and biliary origin
Principal investigator :
Chantal Housset, Ph.D.
Research team :
Axelle Cadoret, Yvon Calmus, Olivier Chazouillères, Nicolas Chignard, Yves Chrétien, Filomena Conti, Christophe Corpechot, Laura Fouassier-Hucko, Christèle Debois-Mouthon, Chantal Housset, Michèle Maurice, Thierry Poynard, Vlad Raziu, Olivier Rosmorduc, Dominique Thabut et Dominique Wendum.
UMR_S938, Centre De Recherche Saint-Antoine, Biliary Pathologies, Fibrosis and Liver Cancer
We assembled large cohorts of patients with biliary diseases caused by gene defects in the phosphatidyl-choline transporter ABCB4, allowing for genotype-phenotype correlations and screening for other mutated genes. The mechanisms of ABCB4 traffic and function, effects of missense variations and pharmacological rescue will be investigated using polarized cell models, Abcb4-/- mice and 3D structure modeling. Interrelations between lipid/bile acid homeostasis, gut microbiota and liver fibrosis, will be examined in Abcb4-/-, Cftr-/- and Vdr-/- mice, challenged with biliary-type injury or high-fat diet and in patients with inflammatory biliary diseases or NAFLD. The paradigm of myofibroblast populations with specialized functions in
liver wound healing, fibrosis and angiogenesis will be addressed in vitro and by cell injection in animal models of liver injury. New markers identified by transcriptomic analyses of the two cell populations will be used for immunohistochemical analyses, cell fate-mapping and ultimately for cell depletion, in transgenic mice. The anti-fibrotic potential of new molecules will be tested in experimental models including human liver myofibroblasts and in therapeutic trials for patients with biliary diseases or NAFLD. Strategies combining Fibrotest, other blood parameters (i.e. bile acid profiles) and elastometry will be designed to assess fibrosis in these populations. An objective is also to build a multivariate prognostic index, based on biomarkers of liver fibrosis and of vascular lesions in large cohorts of obese, type 2 diabetic or hyperlipemic patients, to predict cardiovascular and liver mortality. The project is well integrated in national (Reference centers, ICAN) and international (FP7-FLIP & SAFE-T, iPSCsg) programs.
The objective is to generate concepts and promote their translation into predictive and antifibrotic strategies in liver diseases, ranging from rare biliary disorders to non-alcoholic fatty liver disease (NAFLD).
1. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T; LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008;135:100-10 (159 citations). Comment in:Gastroenterology 2008;135:2156.
2. D’Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009;136:1435-43. Comment in: Gastroenterology 2009;136:1164-1167.
3. Bosselut N, Housset C, Marcelo P, Rey C, Burmester T, Vinh J, Vaubourdolle M, Cadoret A, Baudin B. Distinct proteomic features of two fibrogenic liver cell populations: hepatic stellate cells and portal myofibroblasts. Proteomics 2010;10:1017-1028.
4. Gautherot J, Durand-Schneider A-M, Delautier D, Delaunay J-L, Rada A, Gabillet J, Housset C, Maurice M, Aït-Slimane T. Effects of cellular, chemical and pharmacological chaperones on the rescue of a trafficking-defective mutant of the ATP-binding cassette transporters ABCB1/ABCB4. J Biol Chem
5. Debray D, Rainteau D, Barbu V, Rouahi M, El Mourabit H, Lerondel S, Rey C, Humbert L, Wendum D, Cottart C-H, Dawson P, Chignard N, Housset C. Gallbladder shunt revealed by abnormal bile acid homeostasis in cftr-deficient mice. Gastroenterology 2012;142(7):1581-91. Comments in: Nat Rev Gastroenterol Hepatol 2012;9:188; Gastroenterology 2012 ;142(7):1416-9 & In Press.