Bioinformatics as tool to identify gene/protein-pathways associated with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis


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Bioinformatics as Tool to Identify Gene/Protein-Pathways Associated with Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

To the Editor:

Non-alcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver diseases ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH).1, 2 Because the prevalence of these diseases is increasing, determination of early diagnostic markers as well as development of a more efficient therapy is urgently required. Although obesity, insulin resistance, diabetes, and hypertriglyceridemia are often associated with NAFLD/NASH, the pathogenic mechanisms that lead to NAFLD and its progression to NASH are still unclear.3 Actually, several studies point to genetic predisposition and/or lifestyle-associated factors, which can help to characterize gene/protein-pathways involved in NAFLD/NASH development.4, 5 However, NAFLD/NASH are liver diseases with multiple genetic and environmental determinants; thus, the analysis of a large number of genes and proteins could help to identify not only molecular pathways that are active in NAFLD/NASH, but also those that may contribute to the progression from fatty liver to NASH. Obviously, a single genetic approach is not sufficient to give a comprehensive analysis of these hepatic dysfunctions, but rather, a multiple-approach combination is required.

An example of good integration of various technologies to define pathogenic mechanisms leading to NAFLD/NASH has been reported in a recent article in Hepatology.6 The study integrates a systems biology approach with reverse-phase protein microarray (RPA) analysis to study the role of omental adipose tissue on the development of NAFLD/NASH. Although, earlier studies on NAFLD have focused on histological or molecular analyses of the liver tissue, in this work, the authors used a novel approach to elucidate the pathogenesis of NAFLD.7, 8 Calvert et al. employ RPA to investigate intracellular signaling of omental adipose tissue from patients with NAFLD/NASH. The analysis of 54 molecular targets (kinases and their dependent substrates) demonstrated that phosphorylation of the components of the insulin pathway was more pronounced in the adipose tissue of patients with simple steatosis than in patients with NASH and, furthermore, the derangement of specific insulin-dependent pathways in adipose tissue permitted the investigators to discriminate patients with NASH from those with the nonprogressive forms of NAFLD. All reported data support the hypothesis that adipose tissue plays a biologically active role in liver diseases that depend on alterations of signal transduction pathways related to obesity and/or insulin resistance. The authors underlined the importance of comparing their findings with future studies that should be extended to the analysis of signaling pathways activated in liver tissue. In addition, if their results are validated in large clinical studies, it will provide not only new information about the pathogenesis of NAFLD/NASH, but will also permit the identification and characterization of novel targets and disease markers for pharmacological intervention, gene therapy, and diagnosis.

We believe the relevance of the study presented by Calvert and colleagues is linked to the well-selected combination of bioinformatics and gene/protein expression array analysis. However, it is also clear that characterizing gene-gene and protein-protein interactions, and identifying genetic interactions with environmental conditions, will play an important role in ultimately describing the genetic architecture of NAFLD/NASH.

Anna Alisi Ph.D.*, Matilde Marcellini M.D.*, Valerio Nobili M.D.*, * Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.