Equipe 8

Team 8: Philippe Gual – Albert Tran
HEPATIC COMPLICATIONS IN OBESITY (NAFLD)

Previous activities
The aim of the present team, composed of clinicians and basic scientists, is to better understand the hepatic complications of obesity, one of the most common forms of chronic liver diseases. The hepatic complications of obesity range from steatosis to steatohepatitis (Non Alcoholic SteatoHepatitis, NASH), fibrosis, cirrhosis and finally hepatocellular carcinoma. The diagnosis of steatohepatitis requires a liver biopsy. The pathophysiological mechanisms of the progression of steatosis to steatohepatitis are complex, including insulin-resistance, oxidative stress and endoplasmic reticulum stress. An imbalance between anti- and pro-inflammatory factors might be the triggering step. These factors can originate from intra- or extra-hepatic sites, particularly the adipose tissue.
Research Projects
Our main objectives are: 1) To develop a non invasive index from clinical data and the identified markers of inflammation, apoptosis and necrosis allowing the diagnosis of NASH in obese patients. This will be done in our cohort of 800 morbid obese patients, for whom hepatic and adipose tissue biopsies have been obtained while undergoing a therapeutic bariatric surgery. 2) To study the role of genes previously identified and new players in the progression from steatosis to NASH, fibrosis and hepatocellular carcinoma. The role of theseplayers/factors will be evaluatedin different cellular and animal models. 3) To study the development of the liver complications in achondroplasia in different cellular and animal models. 4) To evaluate and better understand the effect of pharmacological and chirurgical treatment on prevention and correction of liver complications in animal models. The results of the present project should bring new insights in the overall understanding of the mechanistic of hepatic complications induced by obesity and to propose better diagnostic and therapeutic approaches.
Major Publications
2015 Anty R, Canivet CM, Patouraux S, Ferrari-Panaia P, Saint-Paul MC, Huet PM, Lebeaupin C, Iannelli A, Gual P, Tran A. Severe Vitamin D Deficiency May be an Additional Cofactor for the Occurrence of Alcoholic Steatohepatitis. Alcohol Clin Exp Res. 2015 May 2 2014 Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver disease. Biomed Res Int. 2014;2014:120179. Sep 10. Review. Anty R, Tonohouan M, Ferrari-Panaia P, Piche T, Pariente A, Anstee QM, Gual P, Tran A. Low Levels of 25-Hydroxy Vitamin D are Independently Associated with the Risk of Bacterial Infection in Cirrhotic Patients. Clin Transl Gastroenterol.2014 May 29 Patouraux S, Rousseau D, Rubio A, Bonnafous S, Lavallard VJ, Lauron J, Saint-Paul MC, Bailly-Maitre B, Tran A, Crenesse D, Gual P. Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice. Cell Death Dis. 2014 May 2013 Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Patouraux S, Tran A, Gual P, Le Marchand-Brustel Y, Gennero I, Gouze E. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med. 2013 Sep 18;5(203) Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C. M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and non-alcoholic fatty liver disease. Hepatology. 2013 Jul 6. Tran A, Gual P. Non-alcoholic steatohepatitis in morbidly obese patients. Clin Res Hepatol Gastroenterol. 2013 Feb;37(1):17-29. Review. Vazquez-Chantada M, Gonzalez-Lahera A, Martinez-Arranz I, Garcia-Monzon C, Regueiro MM, Garcia-Rodriguez JL, Schlangen KA, Mendibil I, Rodriguez-Ezpeleta N, Lozano JJ, Pedersen O, Banasik K, Justesen JM, Joergensen T, Witte DR, Laurintzen T, Hansen T, Veyrie N, Clement K, Tordjman J, Tran A, Le Marchand-Brustel Y, Buque X, Aspichueta P, Echevarria-Uraga JJ, Martin-Duce A, Caballería J, Gual P, Castro A, Mato JM, Martinez-Chantar ML, Aransay AM, Implication of soluble carrier family 2 member 1 (SLC2A1) in the development of Non-Alcoholic fatty liver disease. Hepatology. 2013 Feb;57(2):505-14. IF: 11.66 2012 Anty R, Marjoux S, Iannelli A, Patouraux S, Schneck AS, Bonnafous S, Gire C, Amzolini A, Ben-Amor I, Saint-Paul MC, Mariné-Barjoan E, Pariente A, Gugenheim J, Gual P, Tran A. Regular coffee but not Espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women patients with NAFLD undergoing bariatric surgery. J of Hepatology, 2012, 57(5):1090-6. IF: 9.26 Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumié A, Gual P$, Wakkach A$ (co-last authors). Identification of Adipose Tissue Dendritic Cells Correlated With Obesity-Associated Insulin-Resistance and Inducing Th17 Responses in Mice and Patients. Diabetes. 2012;61(9):2238-47. IF: 8.28 Patouraux S, Bonnafous S (co-first authors), Voican CS, Anty R, Saint-Paul MC, Rosenthal-Allieri MA, Agostini H, Njike M, Barri-Ova N, Naveau S, Le Marchand-Brustel Y, Veillon P, Calès P, Perlemuter G, Tran A, Gual P. The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One, 2012;7(4):e35612. IF: 4.09 2011 Zimmermann E, Anty R, Tordjman J, Verrijken A, Gual P, Tran A, Iannelli A, Gugenheim J, Bedossa P, Francque S, Le Marchand-Brustel Y, Clement K, Van Gaal L, Sørensen TIA and Jess T. C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients. J of Hepatology, 2011;55(3):660-5. IF: 9.26 Lavallard VJ, Bonnafous S(co-first authors), Patouraux S, Saint-Paul MC, Rousseau D, Anty R, Le Marchand-Brustel Y, Tran A, Gual P. Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease. PLoS ONE, 2011, 6(3), e17599 IF: 4.09 Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V, Varki NM, Wang H, Feng GS. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell. 2011 May 17;19(5):629-39. IF: 26.56 2010 Jager J, Grémeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF. The Tpl2 kinase is up-regulated in adipose tissue in obesity and mediates IL-1β and TNF-α effects on ERK activation and lipolysis. Diabetes, 2010; 59(1):61-70. IF: 8.28 Barr J, Vázquez-Chantada M, Alonso C, Pérez-Cormenzana M, Mayo R, Galán A, Caballería J, Martín-Duce A, Tran A, Wagner C, Luka Z, Lu SC, Castro A, Le Marchand-Brustel Y, Martínez-Chantar ML, Veyrie N, Clément K, Tordjman J, Gual P, Mato JM. Liquid Chromatography-Mass Spectrometry-Based Parallel Metabolic Profiling of Human and Mouse Model Serum Reveals Putative Biomarkers Associated with the Progression of Nonalcoholic Fatty Liver Disease. J Proteome Res., 2010; 9(9):4501-12. IF: 5.11 Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, Gugenheim J, Barr J, Mato JM., Le Marchand-Brustel Y, Tran A and Gual P. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and Nash in morbidly obese patients. PLoS ONE, 2010, 5(10), e13577 IF: 4.09 Anty R, Iannelli A, Patouraux S, Bonnafous S, Lavallard VJ, Senni-Buratti M, Ben Amor I, Staccini-Myx A, Saint-Paul MC, Berthier F, Huet PM, Le Marchand-Brustel Y, Gugenheim J, Gual P, Tran A. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients.. Alimentary Pharmacology& Therapeutics, 2010, 32(11-12), 1315–1322 IF: 3.76 2009 Bertola, A., V. Deveaux, S. Bonnafous, D. Rousseau, R. Anty, A. Wakkach, M. Dahman, J. Tordjman, K. Clement, S.E. McQuaid, K.N. Frayn, P.M. Huet, J. Gugenheim, S. Lotersztajn, Y. Le Marchand-Brustel, A. Tran, and P. Gual. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes. 2009; 58:125-33. IF: 8.28 Iannelli, A., R. Anty, T. Piche, M. Dahman, P. Gual, A. Tran, and J. Gugenheim. Impact of laparoscopic Roux-en-Y gastric bypass on metabolic syndrome, inflammation, and insulin resistance in super versus morbidly obese women. Obes Surg. 2009; 19:577-82. IF: 3.28 2008 Defamie, V., M. Laurens, D. Patrono, L. Devel, A. Brault, M.C. Saint-Paul, A. Yiotakis, P. Barbry, J. Gugenheim, D. Crenesse, V. Dive, P.M. Huet, and B. Mari. Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury. Hepatology. 2008; 47:177-85. IF: 11.66 Piche, T., M.C. Saint-Paul, R. Dainese, E. Marine-Barjoan, A. Iannelli, M.L. Montoya, J.F. Peyron, D. Czerucka, F. Cherikh, J. Filippi, A. Tran, and X. Hebuterne. Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome. Gut. 2008; 57:468-73. IF: 10.11 Anty, R., M. Dahman, A. Iannelli, P. Gual, A. Staccini-Myx, I.B. Amor, N. Luciani, M.C. Saint-Paul, P.M. Huet, J.L. Sadoul, S.K. Srai, R. Unwin, J. Gugenheim, Y. Le Marchand-Brustel, A. Tran, and S. Bekri. Bariatric surgery can correct iron depletion in morbidly obese women: a link with chronic inflammation. Obes Surg. 2008;18:709-14. IF: 3.28 2007 Nousbaum, J.B., J.F. Cadranel, P. Nahon, E.N. Khac, R. Moreau, T. Thevenot, C. Silvain, C. Bureau, O. Nouel, C. Pilette, T. Paupard, G. Vanbiervliet, F. Oberti, T. Davion, V. Jouannaud, B. Roche, P.H. Bernard, S. Beaulieu, O. Danne, D. Thabut, C. Chagneau-Derrode, V. de Ledinghen, P. Mathurin, A. Pauwels, J.P. Bronowicki, F. Habersetzer, A. Abergel, J.C. Audigier, T. Sapey, J.D. Grange, and A. Tran. Diagnostic accuracy of the Multistix 8 SG reagent strip in diagnosis of spontaneous bacterial peritonitis. Hepatology. 2007;45:1275-81. IF: 11.66 Bertola, A., S. Bonnafous, M. Cormont, R. Anty, J.F. Tanti, A. Tran, Y. Le Marchand-Brustel, and P. Gual. Hepatocyte growth factor induces glucose uptake in 3T3-L1 adipocytes through A Gab1/phosphatidylinositol 3-kinase/Glut4 pathway. J Biol Chem. 2007; 282:10325-32. IF: 5.32 2006 Bekri, S., P. Gual, (Co first authors) R. Anty, N. Luciani, M. Dahman, B. Ramesh, A. Iannelli, A. Staccini-Myx, D. Casanova, I. Ben Amor, M.C. Saint-Paul, P.M. Huet, J.L. Sadoul, J. Gugenheim, S.K. Srai, A. Tran, and Y. Le Marchand-Brustel. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006; 131:788-96. IF: 11.67 Anty, R., S. Bekri, N. Luciani, M.C. Saint-Paul, M. Dahman, A. Iannelli, I.B. Amor, A. Staccini-Myx, P.M. Huet, J. Gugenheim, J.L. Sadoul, Y. Le Marchand-Brustel, A. Tran, and P. Gual. The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH. Am J Gastroenterol. 2006; 101:1824-33. IF: 7.28

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