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Tipping the Balance: Hepatotoxicity and the Four Apical Key Events of Hepatic Steatosis
Citation:
Angrish, M., Jonathan-Phillip Kaiser, C. McQueen, AND B. Chorley. Tipping the Balance: Hepatotoxicity and the Four Apical Key Events of Hepatic Steatosis. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 150(2):261-268, (2016).
Impact/Purpose:
Fatty liver (FL) disease is a growing epidemic and currently affects 20–30% of the U.S. population, making it the most common liver disease in the U.S. Furthermore, FL is associated with obesity, diabetes, metabolic syndrome, cardiovascular disease, and certain types of cancer, making FL a major public health concern and a target for preventive strategies. One approach to reduce FL risk is to restrict exposure to environmental chemicals. Data linking chemicals to FL etiology have been used by the U.S. EPA’s Integrated Risk Information System (IRIS) database to derive reference values that help characterize public health risks and support risk management decisions. The challenge is to develop a testing paradigm that is predictive of hepatic steatosis. In this review, we developed an AOP network (AOPnet) that captures the biological complexity of FL disease. This AOPnet consists of interconnected AOPs that are defined by four apical KEs; hepatic fatty acid uptake, de novo fatty acid and lipid synthesis, fatty acid oxidation, and lipid efflux, that branch into interconnected, proximal key events (KEs), key event relationships, and molecular initiating events. This AOPnet will aid biological target identification and assay development initiatives while providing a framework for chemical prioritization based on the likelihood to induce steatosis. Future efforts should concentrate on three major areas to ultimately utilize the FL AOPnet for risk assessment and chemical prioritization: 1) AOPnet development via expert curation of published research and computationally-derived analysis of toxicogenomic databases; 2) AOPnet validation and integration into high throughput testing by designing and validating research models and methodology for KEs amenable to high-throughput and high-content screening; 3) AOPnet application by utilizing testing data to prioritize chemical concern and by integrating PBPK and ADME models with population specific data to predict FL in at-risk human populations to chemical exposure.
Description:
Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk research. According to the Organization for Economic Cooperation and Development (OECD) guidelines, AOPs are pathways with one MIE linked by key events (KEs) to an adverse outcome (AO); however, this approach does not always capture the cumulative impacts of multiple MIEs on the AO. For example, hepatic lipid flux due to chemical-induced toxicity initiates from multiple ligand-activated receptors and signaling pathways that cascade across biology to converge upon a common outcome of fatty liver (also known as hepatic steatosis). To partially capture this complexity, work was initiated to develop a fatty liver AOP network (AOPnet) that includes multiple MIEs and branching KEs defined by four apical KEs: hepatic fatty acid uptake, de novo fatty acid and lipid synthesis, fatty acid oxidation, and lipid efflux. This integrative AOPnet will provide an evidence-based framework to help indicate whether or not chemical-induced effects, as assayed by high-throughput screening, may predict a fatty liver outcome. From a public health standpoint, limiting chemical exposures that contribute to the etiology of fatty liver is an important step in the prevention of serious and potentially progressive liver disease (steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma), as well as extra-hepatic diseases related to metabolic syndrome and systemic energy metabolism.
