The effects of dietary iron on hepatic glucose metabolism and circadian rhythm

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Simcox, Judith Anne
Title The effects of dietary iron on hepatic glucose metabolism and circadian rhythm
Date 2014-05
Description Iron is a micronutrient important in energy homeostasis. Due to its oxidative capacity, it serves as the active site for many redox enzymes both as a component of iron sulfur clusters and heme, and iron-containing proteins are found in biochemical pathways important in energy utilization such as the citric acid cycle and the electron transport chain. The oxidative properties of iron can also be toxic since reduced iron is able to undergo Fenton chemistry to catalyze the formation of reactive oxygen species (ROS). At normal levels, ROS serves a signaling function important for a diverse array of processes, including cellular differentiation, metabolic adaptation, and innate immunity. Excess ROS can produce oxidative stress that affects those pathways and can also oxidize lipids, proteins, and nucleic acids. Herein we explored the role of dietary iron in glucose metabolism both as it affects adenosine monophosphate-activated protein kinase (AMPK) and the circadian factor Rev-Erbα. In the study of both of these proteins, we found that moderate increases in dietary iron are able to create a shift in the oxidative potential of the cell as measured by increased levels of protein carbonylation, and decreased levels glutathione (GSH), and a decreased ratio of reduced to oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP+). Through changes in cellular oxidation, iron is able to alter Sirtuin 1 (Sirt1) activity to deacetylate serine threonine kinase B1(LKB1), which is known to cause a shift from nuclear to cytosolic localization to then increase activation of AMPK. Iron's effects on oxidation also increase transcription of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which promotes transcription of the rate-limiting enzyme in heme synthesis, Aminolevulinate synthase 1 (ALAS-1). Increases in heme levels increase the nuclear receptor subfamily 1, group D, member 2 (Rev-Erbα) and nuclear receptor corepressor (NCOR) complex formation. The increased activity of AMPK and Rev-Erbα with increased dietary iron altered changes in whole body glucose metabolism by decreasing gluconeogenesis to improve glucose tolerance. These results indicate that dietary iron is able to modulate multiple pathways to alter glucose homeostasis, and suggest that more work is needed to gain a full understanding of the optimal levels of iron and how they impact physiology.
Type Text
Publisher University of Utah
Subject MESH Iron, Dietary; Micronutrients; Circadian Rhythm; Homeostasis; Heme; Heme Oxygenase-1; Gluconeogenesis; AMP-Activated Protein Kinases; Liver Glycogen; Diabetes Mellitus, Type 2; Fatty Liver; Insulin Resistance; Reactive Oxygen Species; Oxidative Stress; Glucose Metabolism Disorders
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of The Effects of Dietary Iron on Hepatic Glucose Metabolism and Circadian Rhythm
Rights Management Copyright © Judith Anne Simcox 2014
Format Medium application/pdf
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6pp3bmz
Setname ir_etd
ID 1353908
Reference URL https://collections.lib.utah.edu/ark:/87278/s6pp3bmz
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