Cell Metabolism
Volume 16, Issue 5, 7 November 2012, Pages 634-644
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Article
Metabolomics Identifies an Inflammatory Cascade Involved in Dioxin- and Diet-Induced Steatohepatitis

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Summary

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.

Highlights

▸ Dioxin altered hepatic CES3, resulting in elevated serum azelaic acid monoesters ▸ Decreased CES3 expression is due to proinflammatory cascade activation ▸ The CES3-mediated metabolic changes are associated with steatohepatitis ▸ Azelaic acid monoester is an indicator of dioxin exposure and steatohepatitis

Cited by (0)

4

Present address: Department of Anatomy and Regenerative Biology, Osaka City University, Osaka 545-8585, Japan

5

Present address: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA

6

These authors equally contributed to this work