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Title: An investigation into putative mechanisms underlying the effects of α-tocopherol and its metabolites on the adaptive stress response in HepG2 cells
Author: Banks, Ruth
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2013
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Genes involved in xenobiotic metabolism and antioxidant signaling are enhanced in the liver of long-lived models, suggesting that a link exists between increased stress resistance and longevity assurance. The ability of certain dietary components such as electrophiles and molecules with high redox potential to induce low-dose stimulation of the endogenous cellular adaptive response is proposed to confer increased resistance to environmental stressors, and thereby present a strategy for lifespan assurance. Recently the term ‘hormetics' was applied to dietary antioxidants possessing this activity, in particular those functioning as indirect antioxidants through the induction of stress responsive pathways. Despite recognition of vitamin E as an essential micronutrient in the diet, very little is still known about its biological role, therefore further investigation into its signaling properties and those of its metabolites are required. This thesis details an investigation into the potential role of vitamin E and its long-chain metabolites in the cellular adaptive stress response in a representative hepatic cell line (HepG2), with the purpose of identifying preliminary targets to aid further comprehension of the role of vitamin E in human health and disease. A global transcriptomic approach was used to identify genes differentially regulated by alpha-tocopherol, these included candidates involved in phase I and II xenobiotic metabolism, the cellular antioxidant response and DNA damage repair. Determination of intracellular alpha-tocopherol levels indicated that up-regulation of gene targets occurred in a concentration-dependent manner. Furthermore, this induction occurred in the presence of significantly elevated levels of short-chain metabolites, alpha-carboxymethylbutyl-hydroxychroman (CMBHC) and alpha-carboxyethyl-hydroxychroman (CEHC), suggesting that metabolism of alpha-tocopherol may be important for its signaling function in HepG2 cells. The role of long-chain metabolites of alpha-tocopherol in cellular stress responsive signaling was also investigated in HepG2 cells. The long-chain metabolites were found to alter mitochondrial metabolism in a concentration-dependent manner, and subsequently to induce components of the Nrf-2 signaling pathway suggesting that these metabolites may be potential hormetic agents, and require further investigation into their role in human health.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Liver cells ; Stress (Physiology) ; Vitamin E