The aryl hydrocarbon receptor (AHR), also known as the dioxin receptor, was originally characterized as a xenobiotic receptor that senses xenotoxicants. In the first part of my thesis research, I have uncovered an unexpected endobiotic and hepatic role of AHR in fatty liver and energy metabolism. Despite causing severe fatty liver, transgenic activation of AHR protected mice from diet-induced obesity and type 2 diabetes. The endocrine hormone fibroblast growth factor 21 (FGF21) was established as a novel transcriptional target of AHR and mediates the metabolic benefit of AHR. Moreover, the transactivation of FGF21 by AHR contributed to both hepatic steatosis and systemic insulin hypersensitivity, both of which were largely abolished upon FGF21 knockdown. Results from this study may help to establish AHR as a pivotal environmental modifier that integrates signals from chemical exposure in the regulation of lipid and energy metabolism.
The second part of my thesis research is to investigate the function of AHR in promoting hepatic carcinogenesis and to study the mechanisms of its tumor-promoting effect. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through sustained activation of AHR in rodents, but its carcinogenic effect in human has been controversial. This inter-species difference is largely due to different ligand affinity and distinct gene transactivation selectivity and potency. Here I report the oncogenic potential of human AHR in promoting hepatic carcinogenesis. Constitutive activation of human AHR was as efficiently as mouse Ahr in promoting diethylnitrosamine (DEN)-initiated hepatic carcinogenesis in transgenic mice. The growth arrest and DNA damage-inducible gene 45 beta (Gadd45b), a signal molecule inducible to external stress and UV irradiation, is highly induced upon AHR activation and acts as a transcriptional target of AHR. In addition, as an intrinsic coactivator, Gadd45b facilitates the AHR transcription activity, which might play a role in potentiating the tumor promoting effect of AHR.
Taken together, my work has revealed critical functions of AHR in energy homeostasis and hepatic carcinogenesis. It is hoped that understandings of the functions of AHR may help develop AHR-based novel therapeutics in the treatment of metabolic diseases and hepatic carcinogenesis.
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Toxicology, Surgery, Pharmacology|
|Keywords:||Hepatic carcinogenesis, Humanized mice, Metabolic homeostasis, Transcription factor, Transcriptional regulation, Xenobiotic receptor|
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