Study of the molecular mechanisms involved in the progression from NAFLD to NASH

Project Description:

The accumulation of lipids in the liver, that is hepatosteatosis, leads to nonalcoholic fatty liver disease (NAFLD), this process can progress to more severe liver diseases such as nonalcoholic steato-hepatitis (NASH), fibrosis, cirrhosis  and cancer. The term fatty liver identifies a liver in which lipids account for more than 5% of liver wet weight.  This phenomenon is generally believed to result from an imbalance between the hepatic inflow of free fatty acids (FFAs), triglyceride synthesis and excretion. Elevated serum free fatty acid levels contribute to the pathogenesis of obesity, the metabolic syndrome and cardiovascular disease. Where adipocytes have a unique capacity to store excess fatty acids in the form of triglyceride, nonadipose tissues, including liver, do not. Consequently  when fat accumulates, lipids are primarily stored in the cytoplasm as triglycerides (neutral lipids), leading to micro- and macro-vesicular steatosis and balloon cell degeneration. That in  mild or transient cases, fatty change is reversible and has no adverse effects to the organ.  However in severe cases of steatosis  can occur: cell dysfunction, lipotoxicity and apoptosis as well as pathophysiological changes, increasing, in this way,  susceptibility of steatotic liver to injury. The pathogenesis of liver injury and disease progression in nonalcoholic fatty liver disease, however, is poorly understood. The aim of the present project is the study of the underlying molecular mechanisms involved in the progression from Non Alcoholic Fatty Liver Disease (NAFLD) to Non Alcoholic Steato Hepatitis (NASH). We established an vitro model based on fat laden hepatocytes able to reproduce many of the events described in the initiation of NASH such as inflammation, oxidative stress, production of pro-fibrotic mediators, and induction of apoptosis. Moreover, we are also interested in the study of the cross-talk between hepatocytes with other hepatic resident cells such as hepatic stellate cells (HSC) and the initiation of fibrosis.

Scientists involved:

Natalia Rosso, PhD-Senior Researcher (Scientific Coordinator)

Pablo, J. Giraudi, PhD-Post Doctoral fellow from 2012-to date

Norberto, C. Chavez-Tapia, MD-Traslational Hepatology Fellow from 2008 to 2010

Varenka, J. Barbero-Becerra, PhD-Post Doctoral Fellow 2011-2012

Claudio Tiribelli, MD, PhD-FIF Scientific Director

Period: 2008-to date

Funding Source:  European Union Seventh Framework Program (FP7/2007-2013) under grant agreement n° Health-F2-2009-241762FP7-HEALTH

Dr. NC, Chavez-Tapia: was founded by an in house grant from Fondazione Italiana Fegato Fellowship on translational Hepatology (2008-2009) and by Entry Level Fellowship Dame Sheila Sherlock EASL Fellowship Program (2009-2010)

Dr. VJ. Barbero Becerra was founded by an in house grant from Fondazione Italiana Fegato

Partners:

FLIP consortium: Assistance Publique- Hopiteaux de Paris; Biopredictive SAS; ALMA Consulting Group SAS; University Newcastle; University of Bristol; Università di Bologna; Università di Firenze; Università degli Studi di Torino; Università di Modena e Reggio Emilia; Medizinischen Universitaet Graz, Université di Berne; Servicio Andaluz de Salud; Bispebjerg Hospital - Region Hovedstaden; Università di Ancona;  Medizinischen Universitaet Wien

Publications:

1-      Kinetics of the inflammatory response induced by free fatty acid accumulation in hepatocytes Chávez-Tapia, NC; Rosso,N; Uribe,M; Bojalil,R; Tiribelli, C. Annals of Hepatol 2014-Vol. 13 No. 1, 2014: 00-00 in press

2-      NAFLD to NASH: an experimental study on the early events of fibrosis, Barbero-Becerra V.J., Rosso N., Chavez-Tapia N.C., Tiribelli C (T-51). February 2012 Digestive and Liver Disease Vol. 44 Supplement 1, Page S31

3-      Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease Chavez-Tapia, NC; Rosso, N and Tiribelli, C BMC Gastroenterology 2012, 12:20 doi:10.1186/1471-230X-12-20

4-      In vitro models for the study of non-alcoholic fatty liver disease. Chavez-Tapia NC, Rosso N, Tiribelli C. Curr Med Chem. 2011;18(7):1079-84. Review. PMID:21254970

5-      Increased Expression of IL-6 and IL-8 mRNA in Human Immortalized Hepatocytes after fat Overload N. Chavez-Tapia, N. Rosso, C. Tiribelli.2009 J. Hepatology Suppl.1 Vol 50 (256)

 

Poster and Oral Presentations:

1-        Effects of free fatty acids on Hepatocyte-Stellate Cell cross-talk in a new in vitro model of NASH Giraudi, PJ ; Barbero Becerra, VJ; Chavez-Tapia NC ; Pascucci, FA ;Tiribelli, C and Rosso, N. 54th International Conference on the Bioscience of Lipids: Linking Transcription to Physiology in Lipidomics - Bari, Italy - 17/21 September 2013 (Poster Presentation)

2-        Cross-talk between hepatocytes and hepatic stellate during fibrosis initiation in NASH model. Barbero Becerra, VJ ; Giraudi, P. ; Chavez-Tapia N. C.; Tiribelli, C.; Rosso, N. 23rd Conference of APASL Singapore 6th-10th Jun 2013 (Poster Presentation)

3-        Ricerca traslazionale in patologie non virali - AASLD2012 Novità in epatologia –Istituto Veneto Med. Molecolare Padova 18 Jan 2013 Rosso, N; Chavez-Tapia, NC; Tiribelli, C (Oral Presentation)

4-        In vitro model of NAFD/NASH: The pros and the cons. Rosso, N; Chavez-Tapia, N; Tiribelli, C EASL Basic School of Hepatology - Course 7: Hepatocyte Damage & Liver Metabolism 29 Feb.2012 (Oral presentation)

5-       Inflammatory and fibrogenic response of in vitro hepatocytes exposed to fatty acids. Chavez-Tapia, N.C; Rosso, N; Tiribelli, C 60th Annual Meeting of AASLD, Boston, MA, USA Oct-Nov 2009  (Poster Presentation)

 Kinetic of the inflammatory response induced by free fatty acid load in cultured Hepatocytes Sept 2009 Bologna, Italy - EASL Special conference NAFLD/NASH and Related Metabolic Disease. Chavez-Tapia N.; Rosso N.; Tiribelli, C.(Poster Presentation)

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