Date of Award
Doctor of Philosophy
Food Science and Human Nutrition
Kevin L. Schalinske
Methyl group and homocysteine metabolism play a key role in the balance between health and disease. Retinoids or diabetes have been shown to acutely alter hepatic methyl group and homocysteine metabolism, specifically by induction of glycine N-methyltransferase (GNMT), a proposed regulator of methyl group supply and utilization. The effects of chronic retinoid treatment or the progression of diabetes on aberrant methyl group and homocysteine metabolism are not well-characterized. We hypothesized that sustained induction of GNMT, by either retinoids or diabetes, would lead to a functional methyl deficiency, whereby methyl groups would be unavailable for other methyltransferase reactions, such as DNA methylation. The first study investigated effects of all-trans retinoic acid treatment in rats at 5 or 30 umol/kg body weight (3x weekly) for up to 24 wk. Induction of hepatic GNMT by retinoid treatment was observed at all timepoints between two and 24 wk, but there were no significant changes in DNA methylation. Although there was little evidence of hepatotoxicity, chronic administration of retinoids may adversely impact hematopoiesis and antioxidant defense. Two studies were conducted to characterize the early and advanced type 1 and type 2 diabetic conditions, using the streptozotocin-induced and Zucker diabetic fatty rat models respectively. Alterations of methyl group and homocysteine metabolism by diabetes were both tissue- and disease-stage specific. Most interestingly, aberrant DNA methylation was specific to liver and type 1 diabetes resulted in genomic DNA hypomethylation, whereas type 2 diabetes was associated with genomic DNA hypermethylation. In both diabetic conditions, alterations in methyl group and homocysteine metabolism preceded or were concurrent with changes in epigenetic regulation. Although GNMT was upregulated by retinoid treatment and in both diabetic conditions, the effects on DNA methylation status varied. This disparity suggests a role for additional factors impacting epigenetic regulation and future studies should be conducted with the goal of elucidating which factors are most important in the modulation of methyl group and homocysteine metabolism, as well as regulation of DNA methylation patterns. Abnormal epigenetic regulation also represents a possible mechanistic link to the development of the secondary complications of diabetes, which will be addressed in future studies.
Kelly T. Williams
Williams, Kelly T., "Retinoid- and diabetes-induced aberrations of methyl group and homocysteine metabolism including alterations of epigenetic regulation" (2009). Graduate Theses and Dissertations. 11094.