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Abstract
Glutathione is an abundant tripeptide that protects cells from oxidative stress, xenobiotics, and other stressors. It is found primarily in its reduced form, GSH, and is oxidized to its dimer, glutathione disulfide GSSG, during reduction-oxidation reactions. In general, higher concentrations of GSH and GSH/GSSG protect the cell from injury and disease, whereas an altered intracellular GSH/GSSG balance renders the cell susceptible to oxidative stress and activates pro-inflammatory signaling pathways. As a result, perturbations in GSH homeostasis have been linked with the onset and progression of chronic diseases. Recent evidence from rodents and humans has suggested that genes and loci outside of the canonical GSH synthesis and recycling systems may be responsible for regulation of glutathione, and that glutathione levels are heritable throughout aging. Yet to date, no genetic mapping study has been conducted on glutathione traits in a genetically diverse population. Therefore, the objective of this dissertation was to investigate the genetic regulation of the glutathione redox system and identify the effect of glutathione variation on liver health outcomes in an outbred animal model – the Diversity Outbred (DO) mouse – which reflects the genetic diversity of humans. Chapter 3 quantified the natural variation in hepatic glutathione traits and demonstrates that novel loci are responsible for regulating hepatic GSH/GSSG. Chapter 4 presents the impact of the hepatic glutathione variation on functional outcomes of liver health and suggests that loci responsible for hepatic steatosis progression overlap with that of hepatic GSSG and total glutathione. Chapter 5 demonstrates that hepatic and renal glutathione phenotypes vary to a similar degree and have both shared and tissue-specific loci associated with their glutathione status. In total, the studies of this dissertation redefine our knowledge of redox biochemistry regulation and conclude that glutathione is regulated by novel loci external to the basic glutathione synthesis and recycling systems at a tissue-specific level. These results support additional work into the impact of these candidate genes on modulation of glutathione metabolism, oxidative stress, and disease, to better inform therapeutic approaches attempting to rescue and restore GSH levels.