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Role of the antioxidant transcription factor Nrf2 in determining susceptibility to non-alcoholic steatohepatitis in a human liver cell model


Project Description

Non-alcoholic fatty liver disease (NAFLD) is a major public health concern in the UK as it is associated with obesity, and has huge economic significance. It ranges from simple steatosis through to non-alcoholic steatohepatitis (NASH), to cirrhosis and hepatocellular carcinoma [1]. The molecular events driving NASH are unclear, but it most likely entails interplay between oxidative stress, insulin resistance and inflammation, in response to a high-energy diet.

We found that loss of the cap’n’collar bZIP transcription factor Nrf2, which antagonizes oxidative stress by inducing antioxidant genes, profoundly increases the sensitivity of mice to hepatic steatosis and NASH [2]. As anticipated, we found the Nrf2-null animals exhibited decreased expression of antioxidant genes. However, most surprisingly, Nrf2-null animals also showed loss of AMPK signaling and increased expression of genes encoding fatty acid-metabolizing enzymes and enzymes involved in glucose oxidation, suggesting that Nrf2 regulates energy metabolism.

The project will test the hypotheses that Nrf2 controls redox signaling and energy sensing in cells provided with excess nutrients. Moreover, it will explore Nrf2 regulation in human cell models of NAFLD (hepatoblastoma C3A cells treated with LPON, and an induced pluripotent stem cell (iPSC) model) [3]. Human liver tissue will also be used to validate our findings. Models will assess the impact of variable dietary lipids and sugars (reflecting human diet) on cellular redox signaling, AMPK signaling and energy sensing, and the role played by Nrf2 in attenuating these processes. The effects of Nrf2 will be explored by employing genetic and pharmacological up-regulation of the transcription factor, and also siRNA knockdown of Nrf2. Key measures in the models will be oxidative balance of the cell in response to the flux of sugars and free fatty acids either to oxidation via the TCA cycle or to lipogensis, lipid elongation and esterification to triglyceride.

In addition, to the examination of regulation of sugar and lipid metabolism by genetic and pharmacological manipulation of Nrf2, we will explore cross talk between Nrf2 and the NFkappaB/TNFalpha axis, as a mechanism responsible for the switch from steatosis (viewed as successful adaptation) to steato-hepatitis (i.e. a pro-inflammatory state) allowing exploration of the role of candidate therapeutic agents. In particular, the relative importance of redox signaling, ER stress and the inflammasome in triggering an inflammatory response will be examined.


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To apply please send a cover letter, curriculum vitae and two references to:

Funding Notes

Please note this is a self-funded PhD project

References

1. Schreuder TC, et al. Nonalcoholic fatty liver disease: An overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol. 2008;14:2474-86.
2. Chowdhry S, et al. Loss of Nrf2 markedly exacerbates non-alcoholic steatohepatitis. Free Rad. Biol. Med. 2010:48:357-371
3. Lockman KA, et al. Oxidative stress rather than triglyceride accumulation is a determinant of mitochondrial dysfunction in in vitro models of hepatic cellular steatosis. Liver Int. 2012;32:1079-1092

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