THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY
type: CreativeWork
description: Redox maintenance is critical for all biological species. Amplification of mechanisms that reduces oxidative/electrophilic stress promotes health and extends life. Nuclear factor, erythroid derived 2, like 2 (Nrf2) is a master regulator of biochemical mechanisms that respond to oxidative/electrophilic stress. Under basal conditions, Nrf2 is held in an inactive state in the cytoplasm by binding to the cytoskeletal anchoring protein Kelch-like ECH-associated protein 1 (Keap1). Upon generation of oxidative/electrophilic stress, Nrf2 is released from Keap1 and translocates to the nucleus, where it promotes transcription of a battery of cytoprotective genes. The antioxidative role of Nrf2 has been extensively studied for more than ten years, but the global Nrf2 target genes in liver still remain unknown. The present dissertation utilizes a Nrf2 "gene dose-response" model to genetically modulate the levels of Nrf2 in mouse liver, where the transcription profiles in livers of mice with graded Nrf2 activation were correlated with activation of Nrf2-target genes. Thus, the Nrf2-target genes in mouse liver were investigated systematically. Pathway analyses indicate that genes induced by Nrf2 are involved in glutathione synthesis, oxidation/reduction using NADPH as the co-factor, and xenobiotic metabolism. Moreover, mRNA of genes involved in the pentose phosphate pathway and malic enzyme levels had a clear dose-dependent correlation to active levels of Nrf2, indicating that Nrf2 promotes NADPH generation. Among genes suppressed by Nrf2, the majority are involved in lipid synthesis and fatty-acid desaturation. Thus, Nrf2 promotes generation of NADPH, and reduces fatty acid synthesis and desaturation, contributing factors towards protecting liver against environmental oxidative/electrophilic stress. The mRNA abundance of 124 drug processing genes in the Nrf2 "gene dose-response" model was also determined in this dissertation. The results indicate that Nrf2 facilitates electrophi…
abstract: Redox maintenance is critical for all biological species. Amplification of mechanisms that reduces oxidative/electrophilic stress promotes health and extends life. Nuclear factor, erythroid derived 2, like 2 (Nrf2) is a master regulator of biochemical mechanisms that respond to oxidative/electrophilic stress. Under basal conditions, Nrf2 is held in an inactive state in the cytoplasm by binding to the cytoskeletal anchoring protein Kelch-like ECH-associated protein 1 (Keap1). Upon generation of oxidative/electrophilic stress, Nrf2 is released from Keap1 and translocates to the nucleus, where it promotes transcription of a battery of cytoprotective genes. The antioxidative role of Nrf2 has been extensively studied for more than ten years, but the global Nrf2 target genes in liver still remain unknown. The present dissertation utilizes a Nrf2 "gene dose-response" model to genetically modulate the levels of Nrf2 in mouse liver, where the transcription profiles in livers of mice with graded Nrf2 activation were correlated with activation of Nrf2-target genes. Thus, the Nrf2-target genes in mouse liver were investigated systematically. Pathway analyses indicate that genes induced by Nrf2 are involved in glutathione synthesis, oxidation/reduction using NADPH as the co-factor, and xenobiotic metabolism. Moreover, mRNA of genes involved in the pentose phosphate pathway and malic enzyme levels had a clear dose-dependent correlation to active levels of Nrf2, indicating that Nrf2 promotes NADPH generation. Among genes suppressed by Nrf2, the majority are involved in lipid synthesis and fatty-acid desaturation. Thus, Nrf2 promotes generation of NADPH, and reduces fatty acid synthesis and desaturation, contributing factors towards protecting liver against environmental oxidative/electrophilic stress. The mRNA abundance of 124 drug processing genes in the Nrf2 "gene dose-response" model was also determined in this dissertation. The results indicate that Nrf2 facilitates electrophi…
author: Wu, Kai Connie
language: en
keywords: Toxicology, High throughput screening, Liver, Microarray, Nrf2, Oxidative stress
date published: 2012-08-31
date modified: 2026-07-24T02:46:29Z
provider: University of Kansas
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Kansas

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1808/10289