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The nuclear receptor family member peroxisome proliferator-activated receptor alpha (PPAR alpha) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPAR alpha in rodents increases liver cancer incidence, whereas suppression of PPAR alpha 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 PPAR alpha activity was altered. A gene expression signature of 131 PPAR alpha-dependent genes was built using microarray profiles from the livers of wild-type and PPAR alpha-null mice after exposure to three structurally diverse PPAR alpha 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 PPAR alpha signature and a test set of 48 and 31 biosets positive or negative, respectively for PPAR alpha activation; the test resulted in a balanced accuracy of 98%. The signature was then used to identify factors that activate or suppress PPAR alpha in an annotated mouse liver/primary hepatocyte gene expression compendium of similar to 1850 biosets. In addition to the expected activation of PPAR alpha by fibrate drugs, di(2-ethylhexyl) phthalate, and perfluorinated compounds, PPAR alpha 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) PPAR alpha were also identified. This study 1) developed methods useful for future screening of environmental chemicals, 2) identified chemicals that activate or suppress PPAR alpha, and 3) identified factors including diets and infections that modulate PPAR alpha activity and would be hypothesized to affect chemical-induced PPAR alpha activity.