Enantiomers of Lipoic Acid Differentially Affect Nrf2 Activation

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Enantiomers of Lipoic Acid Differentially Affect
Nrf2 Activation

• Kelly Crotty
• Dr. Tory Hagen

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Our bodies are under attack from both external
and internal toxins.
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Nrf2 A Transcription Factor
B zip

• Transcription factor
• Binds to the Antioxidant Response Element (ARE)

• Influences over 200 genes with the ARE
• These genes produce detoxification enzymes and
  antioxidant proteins

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Nrf2 Production and Degradation

• Always being produced
• Almost immediately bound to the protein Keap1 and
  degraded

Nucleus
Cell
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Under stress, Nrf2 returns to the nucleus in
greater amounts to stimulate gene expression.
Nrf2 Activation
Nucleus
Cell
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Lipoic Acid

• Lipoic Acid (LA) positively influences
  Nrf2-driven gene expression.

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The Enantiamers of Lipoic Acid
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Question

• How potent is S-LA compared to the commercially
  available racemic mixture or natural R-LA?

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Methods
Isolate the nuclei of cells that have been
treated with lipoic acid
Measure relative Nrf2 protein levels in the
nucleus through western blot analysis
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Control 50 uM 35 uM
20 uM 10 uM
5 uM
100 kD
50 uM
20 uM
35 uM
10 uM
5 uM
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Implications
R-LA gt R,S-LA gt S-LA in activating Nrf2

• Though R-LA and S-LA have similar structure, they
  activate Nrf2 at completely different
  concentrations

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Future Projects

• Continue the concentration curve until R,S-LA
  and S-LA have also reached saturation
• Add more time points for the time course
• Repeat the time course with R-LA

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• Thank you to
• The HHMI Summer Research Program
• Dr. Kevin Ahern
• Dr. Tory Hagen
• Judy Butler
• Dr. Dove Keith
• Dr. Kate Shay, Eric Smith, Luis Gomez, Dr. Alex
  Michels, Liam Finlay, Dr. Regis Moreau
• and the rest of the Hagen lab