title: Identification of modulators of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) in a mouse liver gene expression compendium.
abstract: The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents increases liver cancer incidence, whereas suppression of PPARα activity leads to hepatocellular steatosis. Analytical approaches were developed to identify biosets (i.e., gene expression differences between two conditions) in a genomic database in which PPARα activity was altered. A gene expression signature of 131 PPARα-dependent genes was built using microarray profiles from the livers of wild-type and PPARα-null mice after exposure to three structurally diverse PPARα activators (WY-14,643, fenofibrate and perfluorohexane sulfonate). A fold-change rank-based test (Running Fisher's test (p-value ≤ 10(-4))) was used to evaluate the similarity between the PPARα signature and a test set of 48 and 31 biosets positive or negative, respectively for PPARα activation; the test resulted in a balanced accuracy of 98%. The signature was then used to identify factors that activate or suppress PPARα in an annotated mouse liver/primary hepatocyte gene expression compendium of ~1850 biosets. In addition to the expected activation of PPARα by fibrate drugs, di(2-ethylhexyl) phthalate, and perfluorinated compounds, PPARα was activated by benzofuran, galactosamine, and TCDD and suppressed by hepatotoxins acetaminophen, lipopolysaccharide, silicon dioxide nanoparticles, and trovafloxacin. Additional factors that activate (fasting, caloric restriction) or suppress (infections) PPARα were also identified. This study 1) developed methods useful for future screening of environmental chemicals, 2) identified chemicals that activate or suppress PPARα, and 3) identified factors including diets and infections that modulate PPARα activity and would be hypothesized to affect chemical-induced PPARα activity.
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: Keiyu
authors.initials: K
authors.lastname: Oshida
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: Naresh
authors.initials: N
authors.lastname: Vasani
authors.affiliation: Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, United States of America.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.affiliation: RegeneMed, San Diego, California, United States of America.
authors.forename: Dawn
authors.initials: D
authors.lastname: Applegate
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: Mitch
authors.initials: M
authors.lastname: Rosen
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Abbott
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, Piscataway, New Jersey, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Guo
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, Piscataway, New Jersey, United States of America.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
authors.affiliation: University of Washington, Seattle, Washington, United States of America.
authors.forename: Curtis
authors.initials: C
authors.lastname: Klaassen
authors.affiliation: National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, North Carolina, United States of America.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
mesh_terms: D000818:Animals; D004032:Diet; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism; D007239:Infections; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D047493:PPAR alpha