title: Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis.
abstract: Hepatic steatosis is a condition were fat accumulates in the liver and it is associated with extra-hepatic diseases related to metabolic syndrome and systemic energy metabolism. If not reversed, steatosis can progress to steatohepatitis and irreversible stages of liver disease including fibrosis, cirrhosis, hepatocellular carcinoma, and death. From a public health standpoint, identifying chemical exposures that may be factors in steatosis etiology are important for preventing hepatotoxicity and liver disease progression. It is therefore important to identify the biological events that are key for steatosis pathology mediated by chemical exposure. In this review, we give a current overview of the complex biological cascades that can disrupt lipid homeostasis in hepatocytes in the context of 4 apical key events central to hepatic lipid retention: hepatic fatty acid (FA) uptake,de novoFA and lipid synthesis, FA oxidation, and lipid efflux. Our goal is to review these key cellular events and visually summarize them using a network for application in pathway-based toxicity testing. This effort provides a foundation to improve next-generation chemical screening efforts that may be used to prevent and ultimately reverse the growing incidence of fatty liver disease in our population.
authors.affiliation: *National Health and Environmental Effects Research Laboratory, Office of Research and Development (ORD), United States Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27709;
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Angrish
authors.affiliation: United States Environmental Protection Agency (US EPA), National Center for Environmental Assessment, Office of Research and Development (ORD), Cincinnati, Ohio 45268.
authors.forename: Jonathan Phillip
authors.initials: JP
authors.lastname: Kaiser
authors.affiliation: *National Health and Environmental Effects Research Laboratory, Office of Research and Development (ORD), United States Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27709;
authors.forename: Charlene A
authors.initials: CA
authors.lastname: McQueen
authors.affiliation: *National Health and Environmental Effects Research Laboratory, Office of Research and Development (ORD), United States Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27709; chorley.brian@epa.gov.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Chorley
mesh_terms: D004785:Environmental Pollutants / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010084:Oxidation-Reduction
chemical_list: D004785:Environmental Pollutants; D005227:Fatty Acids
keywords: adverse outcome pathway; chemical risk assessment.; high-throughput screening assays; mechanistic toxicology; non-alcoholic fatty liver disease; steatosis