THE ROLE OF THE INTESTINE-LIVER AXIS IN TCDD-ELICITED NON-ALCOHOLIC FATTY LIVER DISEASE IN MICE
Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disorders in which simple hepatic lipid accumulation (hepatic steatosis) progresses to steatohepatitis with fibrosis, is approaching epidemic prevalence in the United States. Often considered to be the hepatic manifestation of metabolic syndrome (MetS), NAFLD increases the risk of developing other complex metabolic disorders (e.g. diabetes, cardiovascular disease, hepatocellular carcinoma) and was recently identified as the second leading cause for requiring a liver transplant. Several factors are known to contribute to NAFLD development including genetic determinants, diet, lifestyle choices, and age. Recently, disruptions in circadian rhythm such as shift work, jet lag, and binge eating have also been associated with NAFLD. Moreover, accumulating evidence demonstrates that exposure to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aryl hydrocarbon receptor (AhR) agonists plays an underappreciated role in the development of metabolic disorders. In rodent models, TCDD-elicited AhR activation causes hepatotoxic features resembling human NAFLD including hepatic lipid accumulation, inflammation, and fibrosis, while chronic exposure increases the incidence of hepatocellular carcinoma. Hepatic and intestinal homeostasis are closely linked by portal and enterohepatic circulation, and thus dysregulation of this intestine-liver axis has been associated with NAFLD and other complex metabolic disorders. However, AhR-mediated transcriptional and functional changes along the intestinal tract have not been thoroughly investigated. This report evaluates the role of the intestine-liver axis in the development and progression of AhR-mediated NAFLD in mice orally gavaged with TCDD every 4 days for 28 days. High throughput analyses such as RNA-Sequencing, AhR chromatin immunoprecipitation (ChIP)-Sequencing, and metabolomics were integrated with targeted assessments including protein measurements, serum biochemistry, microbial gene quantification, and functional assays. TCDD-elicited segment-specific changes along the intestinal tract suggest: (i) dysregulation of dietary iron absorption in the duodenum leads to systemic iron overloading, (ii) enhanced lipid digestion and absorption in the jejunum contributes to hepatic lipid accumulation, (iii) increased bile acid reabsorption in the ileum dysregulates enterohepatic circulation, and (iv) increased microbial bile acid metabolism in the colon results in accumulation of hepatotoxic secondary bile acids. AhR activation also increased paracellular permeability in the gastroduodenal and colonic regions, decreased gut motility, and depleted antigen-presenting cells in the intestinal lamina propria, which may promote hepatic inflammation. Moreover, TCDD dampened the rhythmic expression of core hepatic clock regulators and impaired cues (e.g. heme) which entrain hepatic cycling to nutrient availability. In turn, the rhythmicity of the hepatic transcriptome and metabolome was abolished, decoupling hepatic metabolism from feeding/fasting cycles and reducing metabolic efficiency. Collectively, TCDD-elicited alterations along the intestine-liver axis promote several features of AhR-mediated NAFLD including dietary lipid accumulation, oxidative stress, inflammation, bile acid accumulation, and metabolic reprogramming. These studies provide novel insight into the underlying mechanisms involved in AhR-mediated NAFLD, while highlighting the importance of intestine-liver and host-microbiota relationships in complex metabolic disorders.
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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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Fader, Kelly A.
- Thesis Advisors
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Zacharewski, Timothy R.
- Committee Members
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DeWitt, David L.
Kaminski, Norbert E.
McCabe, Laura R.
Wang, John L.
- Date
- 2018
- Subjects
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Biochemistry
Molecular biology
Toxicology
- Degree Level
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Doctoral
- Language
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English
- Pages
- 282 pages
- Permalink
- https://doi.org/doi:10.25335/w2rs-xa94