This 2020 cell study investigated sulforaphane and three transcription pathways:
“Novel findings of this study are:
- AMPK controls only a subset within the Nrf2-dependent transcriptome;
- Altered Nrf2 levels or altered accessibility of regulatory ARE sites do not account for observed differences in target gene transcription between used wt and AMPK −/− cells;
- Rather, AMPK presence/activity ensures reduced Bach1 abundance with preferential Nrf2 over Bach1 binding to regulatory ARE sites, and finally stronger transactivation of selected target genes; and
- AMPK negatively controls bach1 mRNA expression.
In AMPK−/− cells, levels of BTB and CNC homology 1 (Bach1), a competitor of Nrf2 for ARE sites with predominant repressor function, were higher. Bach1 also bound to a greater relative extent to the examined ARE sites when compared to Nrf2.
Observed AMPK-mediated boost in transactivation of a subset of Nrf2 target genes involves downregulation of Bach1 and subsequent favored binding of activating Nrf2 over repressing Bach1 to examined ARE sites.
The discovered link between AMPK and Bach1 as well as the resulting selective influence on Nrf2 target gene expression are compelling and touch existing data:
- Bach1 contributed to expression of only selected Nrf2 target genes in endothelial cells under hypoxic conditions which, in turn, are known to influence AMPK activity.
- Bach1 levels are elevated during aging, in metastatic lung tumors or triple negative breast tumors with concomitant mitochondrial dysfunction, all events also partly connected with AMPK- and/or Nrf2 activity.
These issues strongly advocate for a closer look into interplay between cellular sensors and executors of the oxidative/xenobiotic and metabolic stress response, which likely will uncover additional layers of regulation of cellular stress resilience.”
https://www.frontiersin.org/articles/10.3389/fcell.2020.00628/full “AMPK Enhances Transcription of Selected Nrf2 Target Genes via Negative Regulation of Bach1”
This study hasn’t been cited even once since it was published eleven months ago (update in Part 4). These researchers did a very good job of producing evidence for mechanisms of signaling pathways competing with and complementing each other.
This study provided further details to support Broccoli sprouts activate the AMPK pathway findings that sulforaphane first activates the AMPK pathway on the way to its main effect of Nrf2 pathway activation: