Nonalcoholic fatty liver disease (NAFLD) has a complex pathogenesis that requires an in-depth understanding of diagnostic and prognostic molecular patterns to develop effective clinical treatment strategies. Here, we present the NAFLD map, a comprehensive, web-based to investigate and simulate molecular processes involved in NAFLD progression.

Due to the heterogeneity of the liver, approaches that focus on small-scale models of a few signaling pathways inadequately represent the spatial aspects of disease progression. To this end, we created a disease map and collected experimentally validated molecular interactions to study macro- & micro-scale heterogeneity and disease progression. We developed a multicompartmental agent-based model (ABM) of autonomous but interacting Boolean networks representing heterogeneous liver compartments and cell types. The stochastic distribution of nutrient supply and metabolic activities between compartments allows the simulation of variations in liver metabolism under different conditions. We present the NAFLD Map as an interactive web-based platform comprising over 30 interconnected subnetworks following SBML standards. Network models of digestive processes enable the study of disease progression following changes in nutritional status.

Finally, the integration of models of the immune response, such as from the Atlas of Inflammation Resolution (AIR), could establish links between metabolic changes in liver compartments and inflammation, bridging the gap to nonalcoholic steatohepatitis (NASH). The disease map allows researchers to perform in silico simulations of NAFLD development, defining conditions such as dietary conditions and drug interactions. The impact of changing conditions on NAFLD progression can be visualized through simulations, providing a better understanding of the disease. Our resource supports the simulation of clinical interventions, potentially facilitating the development of improved treatment strategies.

Please note that the NAFLD map is still in development. For any questions, please contact the research team.

Our strategy for constructing a comprehensive NAFLD map involves three main stages:

1. Boolean Modeling: Creating a boolean model highlighting the molecular interactions leading to NAFLD. SBML-standardized molecular interactions are manually curated for processes involved in the progression of NAFLD. The focus lies on hepatic metabolic and inflammatory as well as digestive processes

2. Agent-based Compartmentalization: Using a compartmental model of the liver to simulate macro- and micro-heterogeneity in hepatic processes, favoring NAFLD progression in specific regions. The boolean models of liver pathways are projected to each compartment in the model with individual parameters.

3. Spatial Interactions & Clinical Calibration: Fitting the model parameters to clinical measurements and integrating spatial interactions between compartments in the model such as cellular interactions and nutrient exchange.