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EASL The International Liver Congress 2015

 

Date: 22-26 April 2015

 

Place: Vienna, Austria

 

Attendees from OWL: Dr. Pablo Ortiz, Dr. Cristina Alonso y Miriam Pérez

 

Booth: 420L 

 

ePoster title: A METABOLIC DEFINITION OF NASH AND ITS RESOLUTION BY S-ADENOSYLMETHIONINE IN MAT1A KO MICE

 

Authors: David Fernandez-Ramos1, Ibon Martínez-Arranz2, Rebeca Mayo2, Sebastiaan M van Liempd1, Holger Sann3, Julian Platon4, Mazen Noureddin5, Patricia Aspichueta6, Cristina Alonso2, M Luz Martínez-Chantar1, Shelly C Lu7, José M Mato1

 

1 CIC bioGUNE, Derio, Bizkaia, Spain

2 OWL Metabolomics, Derio, Bizkaia, Spain

3 Abbott Laboratories GmbH, Hannover, Germany

4 Abbott Products Operations, Allschwil, Switzerland

5 Keck School of Medicine, USC, Los Angeles, CA, USA

6 University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain

7 Cedars-Sinai Medical Center, Los Angeles, CA, USA

 

Abstract:

Background & aims. Mat1a KO mice spontaneously develop nonalcoholic steatohepatitis (NASH), which highlights the role of this gene in hepatic energy stores. MAT1A encodes the enzyme that catalyzes the conversion of methionine into S-adenosylmethionine (SAMe), the main biological methyl donor. NASH patients often have reduced expression of MAT1A, indicating that the Mat1a KO mouse model not only recapitulates the histological and metabolic features of NASH but it is also a relevant model to study human NASH. Methods. Here we used NASH Mat1a KO mice (showing ultrasound fatty liver and elevated ALT) to: 1) evaluate if oral SAMe treatment for two months reverts NASH; 2) study the hepatic metabolic phenotype of NASH in Mat1a KO mice treated with placebo or SAMe (over 500 metabolites were analyzed); and 3) obtain a lipid signature of NASH through the serum lipidomic phenotype in Mat1a KO mice. To translate these findings to humans, we examined the presence of this identified lipid signature of NASH in Mat1a KO mouse in the serum of patients with biopsy proven NASH diagnosis. Results. 1) The histological exam of liver samples revealed a marked reduction of steatosis, inflammation, necrosis and fibrosis as well as a normalization of serum ALT after SAMe treatment in Mat1a KO mice. 2) Lipidomic studies show that the main effect of SAMe in NASH treatment is to improve mitochondrial function, which leads to the reestablishment of a normal response to the accumulation of hepatic fatty acids (FA) (increased FA β-oxidation and decreased lipogenesis) and to the reduction of FA and triglyceride content. In addition to this, SAMe reestablished normal bile acid metabolism. 3) We compare the serum lipidomic profile in WT and Mat1a KO mice to generate a serum signature of NASH comprised of 50 metabolites (M-type signature). To translate these findings to humans, we carried out a hierarchical clustering of the serum lipidomic data of 134 patients with biopsy-confirmed NASH. Patients were classified into two well-defined clusters based on optimum average silhouette width: one cluster with an M-type signature that included 78 patients (58.2%) and a second cluster that contained 56 patients (41.8%), which suggests that the target for NASH patients with an M-type signature may be considered when assessing the efficacy of SAMe treatment. Conclusions. These results show that SAMe treatment halted progression of NASH and reverted toward normal histology in Mat1a KO mice.

 

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