A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis.
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.
Kubrusly
Márcia Saldanha
MS
Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil. msk@usp.br
Corrêa-Giannella
Maria Lúcia
ML
Bellodi-Privato
Marta
M
de Sá
Sandra Valéria
SV
de Oliveira
Claudia Pinto Marques Souza
CP
Soares
Iberê Cauduro
IC
Wakamatsu
Alda
A
Alves
Venâncio Avancini Ferreira
VA
Giannella-Neto
Daniel
D
Bacchella
Telesforo
T
Machado
Marcel Cerqueira Cesar
MC
D'Albuquerque
Luiz Augusto Carneiro
LA
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
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