Investigating the role of transcription factor Nrf2 in the pathogenesis of NAFLD

  • K. L. Wood

Student thesis: Master's ThesisMaster of Science


The pathogenesis of non-alcoholic steatohepatitis (NASH) is thought to occur through interacting mechanisms of cellular stress. Lipids accumulate within hepatocytes, making cells more susceptible to insult and less able to respond to challenges, leading to progression from simple steatosis to inflammation.

Endoplasmic reticulum (ER) stress occurs when mis-folded proteins accumulate in the ER lumen and cellular requirement exceeds the capacity of the ER to modify proteins. ER stress activates pathways that act to attenuate stress or prompt apoptosis if ER homeostasis cannot be achieved. The transcription factor nuclear receptor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator that orchestrates the response to oxidative stress by inducing expression of cytoprotective genes. Understanding interactions between oxidative and ER stress may allow further understanding of the pathogenesis of NASH.

The role of Nrf2 in response to ER stress was investigated using mouse epithelial fibroblasts, comparing WT to Nrf2-/- and cells with increased Nrf2 activity. ER stress was induced and expression of ER stress response proteins was analyzed.

Results demonstrate that Nrf2-/- cells have increased expression of ER stress response proteins under basal conditions compared to WT. The response to ER stress also varied with cellular Nrf2 status: Maximal response to glucose deprivation occurred at 4 hours in both WT and Nrf2-/- cells, but occurred at 6hours in cells with increased Nrf2 availability. The magnitude of the response was smaller in Nrf2-/- cells, suggesting that Nrf2-/- cells have less ability to respond to ER stress. It is proposed that Nrf2 is involved in a negative feedback mechanism, whereby increased Nrf2 activity helps to alleviate ER stress and subsequently down-regulates the ER response.
Date of Award2017
Original languageEnglish
SponsorsThe Melville Trust for the Cure and Care of Cancer
SupervisorJohn Dillon (Supervisor) & John Hayes (Supervisor)

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