Date on Master's Thesis/Doctoral Dissertation
Biochemistry and Molecular Biology
Biochemistry and Molecular Biology, PhD
Committee Co-Chair (if applicable)
PCBs; NAFLD; EGFR; liver; signaling
This dissertation describes how poly-chlorinated biphenyls (PCBs) exacerbate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). While PCBs were banned in 1979, they still persist in contaminated biota, including food, and are detected in human plasma and adipose. The body burden of PCBs is associated with elevation of liver enzymes and necrosis markers in humans, characteristic of NAFLD. PCB exposure in high-fat diet fed mice leads to steatohepatitis that recapitulate the findings seen in exposed humans. The global estimate of people diagnosed with NAFLD is up to 1 in 4 people, unrelated to dietary or genetic factors. The hepatic mechanisms most commonly associated with PCB exposures are xenobiotic nuclear receptor activation, followed by changes in xenobiotic metabolism. Other processes must be involved since highly chlorinated PCB congeners are not metabolized and are long-lived in the body. A novel PCB target was elucidated and characterized, being the epidermal growth factor receptor (EGFR). New effectors downstream of EGFR, including NRF2 and HNF4a, were identified and verified. The basic biology of EGFR signaling in the liver was observed, including regulation of glutathione synthesis, gluconeogenesis, and lipid metabolism. A novel therapy for NAFLD was elucidated in this dissertation, as well, which is therapeutically promising, since no available therapies for NAFLD exist. I hypothesize that PCBs act through inhibition of EGFR action promoting NAFLD. The first finding in this work was that PCBs inhibit EGFR signaling in vivo and in vitro. Next PCBs and other chlorinated compounds were found to prevent EGF-EGFR endocytosis in cell-based assays. The third finding demonstrates that in PCB-mediated steatohepatitis, EGFR-NRF2 and EGFR-HNF4a signaling pathways are downregulated, while fibrogenic pathways are upregulated. PCBs were shown to severely disrupt multiple signaling pathways in PCB-mediated liver disease including a loss of 25% of phospho-peptides involved in cellular regulation. Epidermal growth factor (EGF) administration prevented PCB-mediated steatohepatitis and bridging fibrosis, two of the crucial stages of NAFLD. This dissertation is unique in that a mechanism of action for PCBs through EGFR inhibition was characterized biochemically, followed by evaluation of an effective therapeutic intervention that may impact human health interventions for NAFLD.
Hardesty, Josiah, "Epidermal growth factor receptor (EGFR) inhibition by polychlorinated biphenyls contributes to non-alcoholic fatty liver disease (NAFLD)." (2018). Electronic Theses and Dissertations. Paper 3135.
Biochemical Phenomena, Metabolism, and Nutrition Commons, Chemical and Pharmacologic Phenomena Commons, Medical Biochemistry Commons, Medical Toxicology Commons, Nutritional and Metabolic Diseases Commons