Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis

Tsutomu Matsubara, Naoki Tanaka, Kristopher W. Krausz, Soumen K. Manna, Dong Wook Kang, Erik R. Anderson, Hans Luecke, Andrew D. Patterson, Yatrik M. Shah, Frank J. Gonzalez

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) isamong 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.

Original languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalCell Metabolism
Issue number5
StatePublished - Nov 7 2012

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology


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