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Title Molecular Cues Of Pattern-Recognition-Receptor Pathways In Redox-Toxicity-Driven Environmental NAFLD
Publication Date
Degree PhD
Discipline/Department Health Services and Policy Management
Degree Level doctoral
University/Publisher University of South Carolina
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.
Subjects/Keywords Environmental Public Health; Public Health; Molecular cues; pattern recognition receptors; redox-toxicity; NAFLD
Contributors Saurabh Chatterjee
Rights Open Access Dissertation
Country of Publication us
Record ID oai:scholarcommons.sc.edu:etd-4416
Repository south-carolina
Date Retrieved
Date Indexed 2018-11-21
Created Date 2016-06-30 07:00:00

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…development of steatohepatitic injury (12). Research by our Principal Investigator has shown previously that free radical metabolism of the model toxin CCl4 by CYP2E1 causes the release of damage associated molecular patterns (DAMPS) and…

…One of the key components of the inflammatory microenvironment in various disease pathologies is the ionotrophic purinergic receptors (P2 receptors) which respond to the damage associated molecular patterns (DAMPs) (35, 36)…

…NOX2 has also been shown to facilitate recruitment of tolllike receptor 4 to lipid rafts and to help in receptor dimerization and its association with MD2 in several inflammatory diseases(55). Since there is no evidence of the molecular events…

…model toxin CCl4 by CYP2E1 causes the release of damage associated molecular patterns (DAMPS) and increased release of leptin from both hepatic and adipose tissues(8). These studies assume significance since both reactive oxygen…

…MATERIALS AND METHODS Materials: The spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was obtained from Dojindo Molecular Technologies, Kumamoto, Japan. Bromodichloromethane, Collagenase Type IV, apocynin and gadolinium chloride (GdCl3)…

…chemicals were of analytical grade and were purchased from Sigma Chemical Company or Roche Molecular Biochemicals (Mannheim, Germany). All aqueous solutions were prepared using water passed through a Picopure 2UV Plus system (Hydro Services…

…antigen retrieval, permeabilized, and blocked (2% nonfat dry milk, Pierce Biomedical, Rockford, IL). An antibody specific to DMPO nitrone adducts and Alexafluor 568 goat anti-rabbit secondary antibody (Molecular Probes, now Invitrogen…