Matsubara_2012_Cell.Metab_16_634

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 TGFbeta-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 TGFbeta 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 TGFbeta and steatohepatitis.