Metabolomics Identifies an Inflammatory Cascade Involved in Dioxin- and Diet-Induced Steatohepatitis

被引：74

作者：

Matsubara, Tsutomu ^{[1
]}

Tanaka, Naoki ^{[1
]}

Krausz, Kristopher W. ^{[1
]}

Manna, Soumen K. ^{[1
]}

Kang, Dong Wook ^{[2
]}

Anderson, Erik R. ^{[3
]}

Luecke, Hans ^{[2
]}

Patterson, Andrew D. ^{[1
]}

Shah, Yatrik M. ^{[3
]}

Gonzalez, Frank J. ^{[1
]}

机构：

[1] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[2] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA

[3] Univ Michigan, Dept Mol & Integrat Physiol & Internal Med, Div Gastroenterol, Sch Med, Ann Arbor, MI 48109 USA

来源：

CELL METABOLISM | 2012年 / 16卷 / 05期

关键词：

ARYL-HYDROCARBON RECEPTOR; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD; DEFICIENT MICE; DBA/2J MICE; INDUCTION; TOXICITY; TERATOGENESIS; DISRUPTION; MICROARRAY; EXPRESSION;

D O I：

10.1016/j.cmet.2012.10.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 TODD-stimulated TGF beta-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 TGF beta 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, TGF beta, and steatohepatitis.

引用

页码：634 / 644

页数：11

共 24 条

[21] Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1α [J].

Tomita, S ;

Sinal, CJ ;

Yim, SH ;

Gonzalez, FJ .

MOLECULAR ENDOCRINOLOGY, 2000, 14 (10) :1674-1681

[22] Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression [J].

Vorderstrasse, BA ;

Steppan, LB ;

Silverstone, AE ;

Kerkvliet, NI .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2001, 171 (03) :157-164

[23] Cross-talk between IL-6 and TGF-β signaling in hepatoma cells [J].

Yamamoto, T ;

Matsuda, T ;

Muraguchi, A ;

Miyazono, K ;

Kawabata, M .

FEBS LETTERS, 2001, 492 (03) :247-253

[24] Regulation of rat carboxylesterase expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD):: A dose-dependent decrease in mRNA levels but a biphasic change in protein levels and activity [J].

Yang, DF ;

Li, YX ;

Yuan, X ;

Matoney, L ;

Yan, BF .

TOXICOLOGICAL SCIENCES, 2001, 64 (01) :20-27

← 1 2 3 →