Análisis de los mecanismos moleculares asociados al desarrollo de esteatohepatitis no alcohólica y hepatocarcinoma en un modelo de ratón deficiente en el gen matia mediante proteómica funciona. Identificación de biomarcadores

Résumé

#TITULO: ANÁLISIS DE LOS MECANISMOS MOLECULARES ASOCIADOS AL DESARROLLO DE ESTEATOHEPATITIS NO ALCOHÓLICA Y HEPATOCARCINOMA EN UN MODELO DE RATÓN DEFICIENTE EN EL GEN MATlA MEDIANTE PROTEOMICA FUNCIONAL. IDENTIFICACIÓN DE BIOMARCADORES RESUMEN: We have investigated the progression of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) using a proteomic approach in a knockout mi ce deficient in hepatic AdoMet synthesis (MATlA -/-). During the development of NASH, 117 differential proteins were identified by mass spectrometry in the KO liver. Among them, 12 proteins changed their expression from birth to the n'se of histological lesions. Four of these proteins, ATP synthase á chain, cytochrome C oxidase I/II and Prohibitin 1 have known roles in mitochondrial function suggesting a mitochondrial failure at early stages of the disease. These alterations were al so demonstrated in the liver of ob/ob mi ce and obese patients who are at risk for NASH. The analysis of tumor nodules from different MATlA-/- mi ce revealed that more than 10% (p<0.05) of the proteins changed their expression pattern while the variability within any other experimental group was lower than 1% (p<0.01). Our results suggest that proteome heterogeneity not only derives from a stochastic process associated to tumor growth but al so that mouse-specific factors might account for the unstability by imposing a selective pressure on preneoplastic foci. We have identified 151 proteins differentially expressed in MATlA-/- tumors, and 27 are common to more than 50% of the analyzed tumors. Changes at the mRNA level of 15 of these proteins were assessed in the liver of patients who had developed cirrhosis or HCC. Moreover, we had identified an up-regulated isoform of Apolipoprotein A-I ( ApoA-i ) in the serum of MATlA -/- mice much earlier than any histological! manifestation of liver disease. Further characterization of the differential isoform by electrospray tandem mass spectrometry revealed specific oxidation of methionine 85 and 216 to methionine sulfoxide. Enrichment of an acidic isoform of apolipoprotein A-I was all so assessed in the serum of HBV patients who developed hepatocarcinoma. Specific oxidation of methionine 112 to methionine sulfoxide and tryptophan 50 and 108 to formylkinurenine were identified selectively in the up-regulated isoform.