A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis
Márcia Saldanha Kubrusly1,3, Maria Lúcia Corrêa-Giannella2, Marta Bellodi-Privato3, Sandra Valéria de Sá2, Claudia Pinto Marques Souza de Oliveira3, Iberê Cauduro Soares4, Alda Wakamatsu4, Venâncio Avancini Ferreira Alves4, Daniel Giannella-Neto5, Telesforo Bacchella3, Marcel Cerqueira Cesar Machado3 and Luiz Augusto Carneiro D’Albuquerque3
1Department of Surgery, 2Laboratory for Cellular and Molecular Endocrinology (LIM-25), 3Department of Gastroenterology (LIM-37), 4Department of Pathology (LIM-14) and 5Medical Investigation Laboratories (LIM-07), University of São Paulo School of Medicine, São Paulo, Brazil.
Offprint requests to: Dr. Márcia Saldanha Kubrusly, Department of Gastroenterology, School of Medicine, University of São Paulo, Av. Dr. Arnaldo 455 3º andar sala 3223, São Paulo, Brazil. e-mail: firstname.lastname@example.org
Summary. 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. Methods: 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. Results: 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. Conclusions: 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. Histol Histopathol 25, 1123-1131 (2010)
Key words: Cirrhosis, Non alcoholic steatohepatitis, Gene expression profile, Microarray analysis, mTOR pathway