Date of Award

6-30-2016

Document Type

Open Access Dissertation

Department

Health Services and Policy Management

Sub-Department

Norman J. Arnold School of Public Health

First Advisor

Saurabh Chatterjee

Abstract

With the pandemic proportions of obesity and a correlative increase in fatty liver disease, there was a dire need to explore the missing link between the changed environment and progression of NAFLD in obesity. My research implies that environmental toxin bromodichloromethane induces early liver lesions in obesity, and is mediated by the synchronous insult of oxidative stress and increased levels of the adipokine leptin. In a two-pronged approach to investigate the molecular cues, I looked at the role of Purinergic receptor X7 and Toll 4 receptor. Both rodent models and cell-based systems were used. Also, in order to validate my findings in humans, I used diseased liver samples and corresponding age-matched controls. All diseased samples, and toxin-primed cell systems tested positive for oxidative stress markers. My first set of findings strongly suggest that P2X7r is a key regulator of autophagy-induced metabolic oxidative stress and early liver inflammation. In the second part of my investigation, I observed that toll 4 receptor recruitment to raft-zones of the liver cell membranes is crucial for its induction and inflammation in NAFLD. Most importantly, instead of the well-established stimulator of toll-receptor 4, LPS, I show that peroxynitrite which is elevated in the system as a result of the free radical chemistry, post environmental toxin exposure, is a potent inducer of TLR4-mediated inflammation in the disease. High-end confocal microscopy and immunofluorescence imaging techniques were utilized in addition to quantifying gene expressions, and immunoblotting proteins. Also, in a first-ever report in any model of NAFLD I used a peroxynitite-scavenging molecule FBA, showing positive remediation of NAFLD symptoms. This could be a very promising treatment regimen for redox-toxicity driven NAFLD. In conclusion, this novel disease model of NAFLD, helps us better understand the environmental link to the disease in presence of obesity, and exemplifies the molecular cues as potential therapeutic targets for alleviation of this silent-killer.

Rights

© 2016, Suvarthi Das

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