Elucidating Mechanistic Relationships between Peroxisome Proliferator-activated Receptors and Hepatic Fibrosis using the ROBOKOP Knowledge Graph

Karamarie Fecho ^1,2* Nyssa Tucker ³ Jon-Michael Beasley ³ Scott Auerbach ⁴ Chris Bizon ¹ Alexander Tropsha ³

• ¹ Renaissance Computing Institute, Chapel Hill, United States
• ² Copperline Professional Solutions, LLC, Pittsboro, United States
• ³ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ⁴ Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIH), Durham, California, United States

We developed the Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways (ROBOKOP) application as an open-source knowledge graph system to support evidence-based biomedical discovery and hypothesis generation. This study aimed to apply ROBOKOP to suggest biological mechanisms that might explain the hypothesized relationship between exposure to the herbicide and lipid-lowering drug clofibrate, an activator of peroxisome proliferator-activated receptor-α (PPARA), and hepatic fibrosis. We queried ROBOKOP to first establish that ROBOKOP could demonstrate a relationship between clofibrate and PPARA, as a validation test, and second identify intermediary genes and biological processes or activities that might relate the activation of PPARA by clofibrate to hepatic fibrosis. Queries of ROBOKOP returned a number of paths relating clofibrate, PPARA, and hepatic fibrosis. One path suggested the following: clofibrate - affects / increases_ expression_ of / increases_ activity_ of / increases_ response_ to / decreases_ response_ to / is_ related_ to - PPARA -is_ actively_ involved_ in - cellular response to lipid - actively_ involves -CCL2 - is_ genetically_ associated_ with - hepatic fibrosis. This result established a relationship between clofibrate and PPARA and further suggested that: PPARA is actively involved with the cellular response to lipid, which actively involves the chemokine ligand CCL2, which is genetically associated with hepatic fibrosis; thus, we can infer that PPARA, upon activation by clofibrate, is involved with hepatic fibrosis. We conclude that ROBOKOP can be used to derive insights into biological mechanisms that might explain relationships between environmental exposures and liver toxicity.