title: Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is among the most potent environmentally toxic compounds. Serum metabolomics identified azelaic acid monoesters as significantly increased metabolites after TCDD treatment, due to downregulation of hepatic carboxylesterase 3 (CES3, also known as triglyceride hydrolase) expression in an arylhydrocarbon receptor (AhR)-dependent manner in mice. The decreased CES3 expression was accomplished by TCDD-stimulated TGFβ-SMAD3 and IL6-STAT3 signaling, but not by direct AhR signaling. Methionine- and choline-deficient (MCD) diet-treated mice also showed enhanced serum azelaic acid monoester levels after attenuation of hepatic CES3 expression, while db/db mice did not, thus suggesting an association with steatohepatitis. Forced expression of CES3 reversed serum azelaic acid monoester/azelaic acid ratios and hepatic TGFβ mRNA levels in TCDD- and MCD diet-treated mice and ameliorated steatohepatitis induced by MCD diet. These results support the view that azelaic acid monoesters are possible indicators of TCDD exposure and steatohepatitis and suggest a link between CES3, TGFβ, and steatohepatitis.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Soumen K
authors.initials: SK
authors.lastname: Manna
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: Erik R
authors.initials: ER
authors.lastname: Anderson
authors.forename: Hans
authors.initials: H
authors.lastname: Luecke
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000097:blood / Q000378:metabolism; D004032:Diet; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D003998:Dicarboxylic Acids; D015850:Interleukin-6; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D002265:Carboxylic Ester Hydrolases; C010038:azelaic acid