Advances in high-throughput experimental analyses have had a profound impact on biomedical research. As a consequence of the Human Genome Project, the availability of genome sequences has fueled the growth of functional genomics and systems biology/medicine, which, through large-scale integration of databases with existing scientific knowledge represents a substantial gain, since it facilitates scientific progress by identifying new associations and correlations. In this issue of Digestive Diseases and Sciences, Clarke et al. [1] report the characterization of hepatocellular carcinoma (HCC) related genes and metabolites in human nonalcoholic fatty liver disease (NAFLD) using systems biology methods. NAFLD represents a group of multifactorial progressive liver disorders that together represent the predominant worldwide liver disease. The prevalence of NAFLD is increasing rapidly due to the related epidemics of obesity and diabetes. The disease spectrum of NAFLD ranges from simple non-progressive steatosis, to steatohepatitis (NASH), which is a more serious form of liver damage characterized by fibrosis and variable amounts of visible fat. NASH can progress further to cirrhosis and to hepatocellular carcinoma (HCC) [2, 3]. NAFLD was initially considered as the hepatic component of the metabolic syndrome due to its strong associations with insulin resistance and links to visceral obesity. NAFLD is now considered as a multifactorial condition that leads not only to increased liver-related mortality but also to increased risk of the development of type 2 diabetes mellitus and cardiovascular diseases (CVD) [4]. Abnormalities in lipid and lipoprotein metabolism accompanied by chronic inflammation are crucial for development of metabolic syndromerelated diseases where cholesterol as the lipid component lies at the crossroad of NAFLD and atherogenesis. NAFLD-associated pathologies can thus on the one hand be triggered by altered metabolism, such as is associated with insulin resistance or dyslipidemia, while on the other hand NAFLD can itself increase the risk for the development of diabetes mellitus and cardiovascular diseases [4]. This complex network of interactions has common roots in the primary metabolic pathways of the liver and of other tissues. Fatty hepatic infiltration can critically affect hepatic drug metabolism due to alteration of the nuclear receptor network [5], which in turn can affect the severity of NAFLD through alterations of drug metabolism. Despite the apparent common origins of NAFLD, HCC, and T2D, it appears that the differing genetic and environmental factors to which each individual is exposed might explain the inter-individual variability of disease progression. This likely underlies the current discrepancy between the increasingly detailed understanding of the molecular mechanisms of the disease and the inconsistent results of global understanding that would aid clinical interventions. At present, the genome wide association studies (GWAS), transcriptome analyses, meta-analyses and other clinical studies conducted in different populations of varying ethnic backgrounds are concordant in that polymorphisms of PNPLA3 (patatin-like phospholipase domain containing 3) associate with steatosis and progression to NASH and HCC. Since PNLPA3 protein function in lipolysis is not completely understood, the challenge is to understand how loss-of-function PNLPA3 D. Rozman (&) Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia e-mail: damjana.rozman@mf.uni-lj.si