Higher Nrf2 activation may be needed for activating metabolic genes vs. cytoprotective genes
The researchers wanted to test if activating the PI3K-Akt signaling pathway allows the Nrf2 protein to turn on genes involved in metabolism. They did experiments in mouse livers with different genetic modifications:
- Control (normal)
- Pten gene deleted (P-Alb) - activates PI3K-Akt pathway
- Keap1 gene deleted (K-Alb) - allows Nrf2 to accumulate
- Both Pten and Keap1 deleted (P/K-Alb)
They found that:
- “Keap1 gene deleted” livers had a small increase in metabolic gene expression.
- “Pten gene deleted " livers had only a slight increase.
- “Both Pten and Keap1 deleted” livers had a large increase in metabolic gene expression, even for genes not increased in just Keap1 deleted livers.
This suggests that activating PI3K-Akt (by deleting Pten) enhances Nrf2’s ability to turn on metabolic genes when Keap1 is also deleted.
To confirm Nrf2’s role, they repeated the experiments in mice lacking Nrf2:
- P/K-Alb/N (no Nrf2) livers had much lower metabolic gene expression, similar to P-Alb
- P/K-Alb/N-h (half dose of Nrf2) was in between P/K-Alb and P/K-Alb/N
Therefore, Nrf2 is necessary for the increased metabolic gene expression seen when both Pten and Keap1 are deleted. Higher Nrf2 activity is needed to activate metabolic genes compared to cytoprotective genes like Nqo1.
They also measured metabolites in the livers:
- K-Alb was similar to control
- P/K-Alb had lower PPP intermediates, higher IMP and GSH compared to P-Alb
- These changes were reversed in P/K-Alb/N (“Both Pten and Keap1 deleted; no Nrf2”)
This shows that Nrf2 accumulation alters metabolite levels only when the PI3K-Akt pathway is also activated.
Key points:
- Activating PI3K-Akt enhances Nrf2’s ability to induce metabolic genes
- Nrf2 is required for the increased metabolic gene expression
- Higher Nrf2 activity is needed for metabolic genes vs cytoprotective genes
- Nrf2 accumulation changes metabolite levels only with active PI3K-Akt signaling