Investigating the role of transcription factors Nrf2 and Pparα in hepatic lipid metabolism during fasting
type: CreativeWork
description: The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) controls the basal and inducible expression of a plethora of genes, predominantly those associated with oxidative stress response through its regulation of the glutathione and thioredoxin based antioxidant systems, and the maintenance of cellular redox homeostasis. While Nrf2 has long been studied in this context, it has more recently become apparent that the role of Nrf2 goes far beyond this narrow spectrum, including a clear role in the regulation of pathways involved in NADPH generation, gluconeogenesis, and lipid metabolism, although the true extent of the contribution of Nrf2 in vivo to many of these processes has yet to be fully elucidated. When the Nrf2 gene is disrupted, many genes involved in lipogenesis, which are known to be regulated by Pparα, are upregulated, indicating a potential role for Nrf2 in the repression of Pparα, a master regulator of hepatic lipid metabolism. The primary aim of this thesis was to further define the role of Nrf2 during metabolic stress and to determine the mechanism of action of such a function. Genetically altered animals of the genotypes WT, Nrf2-/-, Pparα-/- and Nrf2-/-/::Pparα-/- double knockout were utilised during the course of this study in an effort to tease apart the interactions of transcription factors Nrf2 and Pparα under acute and extended fasting conditions, when Pparα is strongly activated, to better understand their in vivo relationship. Data presented within this thesis demonstrate that during periods of extended fasting, Nrf2 serves to diminish the magnitude of gene induction mediated by Pparα in response to fasting. In Nrf2-/- animals during 48 hr fasting, the level of Pparα target gene expression is significantly higher, with corresponding lower plasma free fatty acid concentration than their WT counterparts. Upon genetic knockout of Pparα the target genes which were upregulated in the Nrf2-/- animals were not induced in respons…
abstract: The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) controls the basal and inducible expression of a plethora of genes, predominantly those associated with oxidative stress response through its regulation of the glutathione and thioredoxin based antioxidant systems, and the maintenance of cellular redox homeostasis. While Nrf2 has long been studied in this context, it has more recently become apparent that the role of Nrf2 goes far beyond this narrow spectrum, including a clear role in the regulation of pathways involved in NADPH generation, gluconeogenesis, and lipid metabolism, although the true extent of the contribution of Nrf2 in vivo to many of these processes has yet to be fully elucidated. When the Nrf2 gene is disrupted, many genes involved in lipogenesis, which are known to be regulated by Pparα, are upregulated, indicating a potential role for Nrf2 in the repression of Pparα, a master regulator of hepatic lipid metabolism. The primary aim of this thesis was to further define the role of Nrf2 during metabolic stress and to determine the mechanism of action of such a function. Genetically altered animals of the genotypes WT, Nrf2-/-, Pparα-/- and Nrf2-/-/::Pparα-/- double knockout were utilised during the course of this study in an effort to tease apart the interactions of transcription factors Nrf2 and Pparα under acute and extended fasting conditions, when Pparα is strongly activated, to better understand their in vivo relationship. Data presented within this thesis demonstrate that during periods of extended fasting, Nrf2 serves to diminish the magnitude of gene induction mediated by Pparα in response to fasting. In Nrf2-/- animals during 48 hr fasting, the level of Pparα target gene expression is significantly higher, with corresponding lower plasma free fatty acid concentration than their WT counterparts. Upon genetic knockout of Pparα the target genes which were upregulated in the Nrf2-/- animals were not induced in respons…
author: Tebay, Lauren
language: eng
date published: 2015
date modified: 2026-07-24T02:08:12Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee