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Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver.

ABSTRACT: Peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested to protect against chemically induced hepatobiliary injuries in rodents. This function could mask the potential toxicities of perfluorooctanoic acid (PFOA) that is an emerging environmental contaminant and a weak ligand of PPARalpha. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Pparalpha-null mice after 4 wk treatment with PFOA ammonium salt (0, 12.5, 25, 50 micromol/kg/d, gavage). In wild-type mice, PFOA caused major hepatocellular damage dose-dependently and minor cholangiopathy observed only at 25 and 50 micromol/kg. In treated Pparalpha-null mice, PFOA produced marked fat accumulation, severe cholangiopathy, hepatocellular damage and apoptotic cells especially in bile ducts. Oxidative stress was also increased 4-fold at 50 micromol/kg and TNF-alpha mRNA was upregulated more than 3-fold at 25 micromol/kg in Pparalpha-null mice. Biliary bile acid/phospholipid ratios were higher in Pparalpha-null mice than in wild-type mice. Results from these studies suggest that PPARalpha is protective against PFOA and have a critical role in drug induced hepatobiliary injury.

SUBMITTER: Minata M

PROVIDER: S-EPMC7385711 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver.

Minata Mutsuko M Harada Kouji H KH Kärrman Anna A Hitomi Toshiaki T Hirosawa Michi M Murata Mariko M Gonzalez Frank J FJ Koizumi Akio A

Industrial health 20100101 1

Peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested to protect against chemically induced hepatobiliary injuries in rodents. This function could mask the potential toxicities of perfluorooctanoic acid (PFOA) that is an emerging environmental contaminant and a weak ligand of PPARalpha. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Pparalpha-null mice after 4 wk treatment with PFOA ammonium salt ...[more]

PMID: 20160413

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Project description: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.

Dataset Information

Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver.

Publications

Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver.

Similar Datasets

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