title: A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis.
abstract: Non-alcoholic fatty liver disease (NAFLD) encompasses the whole spectrum of steatosis, non-alcoholic steatohepatitis (NASH), and NASH-related cirrhosis (NASH/Cir). Although molecular advances have been made in this field, the pathogenesis of NAFLD is not completely understood. The gene expression profiling associated to NASH/Cir was assessed, in an attempt to better characterize the pathways involved in its etiopathogenesis.
  
  
  
  In the first step, we used cDNA microarray to evaluate the gene expression profiles in normal liver (n=3) and NASH/Cir samples (n=3) by GeneSifter analysis to identify differentially expressed genes and biological pathways. Second, tissue microarray was used to determine immunohistochemical expression of phosphorylated mTOR and 4E-BP1 in 11 normal liver samples, 10 NASH/Cir samples and in 37 samples of cirrhosis of other etiologies to further explore the involvement of the mTOR pathway evidenced by the gene expression analysis.
  
  
  
  138 and 106 genes were, respectively, up and down regulated in NASH/Cir in comparison to normal liver. Among the 9 pathways identified as significantly modulated in NASH/Cir, the participation of the mTOR pathway was confirmed, since expression of cytoplasmic and membrane phospho-mTOR were higher in NASH/Cir in comparison to cirrhosis of other etiologies and to normal liver.
  
  
  
  Recent findings have suggested a role for the cellular "nutrient sensor" mTOR in NAFLD and the present study corroborates the participation of this pathway in NASH/Cir. Phospho-mTOR evaluation might be of clinical utility as a potential marker for identification of NASH/Cir in cases mistakenly considered as cryptogenic cirrhosis owing to paucity of clinical data.
authors.affiliation: Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil. msk@usp.br
authors.forename: Márcia Saldanha
authors.initials: MS
authors.lastname: Kubrusly
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.forename: Marta
authors.initials: M
authors.lastname: Bellodi-Privato
authors.forename: Sandra Valéria
authors.initials: SV
authors.lastname: de Sá
authors.forename: Claudia Pinto Marques Souza
authors.initials: CP
authors.lastname: de Oliveira
authors.forename: Iberê Cauduro
authors.initials: IC
authors.lastname: Soares
authors.forename: Alda
authors.initials: A
authors.lastname: Wakamatsu
authors.forename: Venâncio Avancini Ferreira
authors.initials: VA
authors.lastname: Alves
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto
authors.forename: Telesforo
authors.initials: T
authors.lastname: Bacchella
authors.forename: Marcel Cerqueira Cesar
authors.initials: MC
authors.lastname: Machado
authors.forename: Luiz Augusto Carneiro
authors.initials: LA
authors.lastname: D'Albuquerque
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D018797:Cell Cycle Proteins; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases