A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis

Histol Histopathol. 2010 Sep;25(9):1123-31. doi: 10.14670/HH-25.1123.

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.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Biomarkers / analysis
  • Cell Cycle Proteins
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases
  • Tissue Array Analysis

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases