TCDD-elicited metabolic reprogramming in the progression of non-alcoholic fatty liver disease
The prevalence of metabolic disorders such as cardiovascular disease, type II diabetes, and non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in Western societies. Several factors are implicated in the development of these diseases including age, sex, genetics, diet, and lifestyle. In recent years exposure to environmental contaminants has also been linked to the development of metabolic diseases. Notably, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with NAFLD development in epidemiological and rodent studies. TCDD is the prototypical ligand for the aryl hydrocarbon receptor (AhR) which is activated by structurally diverse environmental contaminants, natural products, and endogenous metabolites. In mice, exposure results in the development of hepatic steatosis (fat accumulation) via an AhR dependent mechanism, which is reversed upon cessation of exposure. Continuous TCDD exposure on the other hand leads to collagen deposition indicating progression through the NAFLD disease spectrum (e.g., simple steatosis - steatohepatitis (steatosis with inflammation) – fibrosis/cirrhosis). However, little is known about the mechanism through which AhR activation contributes to NAFLD disease etiology. The advent of high-throughput and data rich ‘omics’ technologies have facilitated the large-scale assessment of molecular responses and mechanisms of action through the integration of disparate datasets and use of enrichment and systems biology approaches. The present report evaluates the time- and dose-dependent progression of TCDD-elicited NAFLD pathology in mice gavaged with TCDD every 4 days for 28 or 92 days. ‘Layers’ of biological organization are interrogated through the computational identification of genome-wide dioxin response elements (DREs), chromatin immunoprecipitation sequencing (ChIP-Seq), total RNA sequencing (RNA-Seq), targeted metabolomics, and quantitative evaluation of histological features using the in-house developed Quantitative Histological Analysis Tool (QuHAnT). Systems biology based approaches were used to integrate these disparate datasets to elucidate a mode of action underlying TCDD-elicited disease progression revealing a coordinated reorganization of hepatic gene expression and metabolism characterized by 1) a Warburg effect-like reprogramming of carbohydrate metabolism in an AhR-dependent manner, 2) amino acid metabolism redirection, and 3) widespread inflammatory and matrisomal gene expression changes. These metabolic changes underlie the time- and dose-dependent progression of hepatic steatosis to steatohepatitis, and collagen deposition (fibrosis) providing evidence that persistent AhR activation can promote NAFLD pathology progression. Ultimately, these studies indicate complex reprogramming of hepatic metabolism resulting from AhR activation that include not only the promotion of disease progression, but also novel defensive counter measures in an attempt to reduce TCDD-elicited hepatotoxicity.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Nault, Rance
- Thesis Advisors
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Zacharewski, Timothy R.
- Committee Members
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Chan, Christina
Henry, Bill
Jones, Daniel
Kaminski, Norbert E.
- Date
- 2016
- Degree Level
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Doctoral
- Language
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English
- Pages
- xii, 168 pages
- ISBN
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9781339989518
1339989514