Fig. 8.

Mechanisms linking Nur77 activation by FA and insulin gene control in Min6 cells. Upon activation and nuclear translocation of Nur77, this orphan NR engages physical interaction with the FoxO1 transcriptional regulator bound to its upstream DNA binding sequence located in the 5′-mafA gene-regulatory sequence. This interaction leads to a decreased intracellular concentration of the mafA protein. This, in turn, prevents activation of the insulin gene, which is critically regulated by mafA, causing a decreased intracellular insulin concentration and impaired insulin secretion. Other mechanisms potentially interfering with insulin maturation and release (Zinc homeostasis) or signaling pathways affecting β-cell responses or architecture are indicated, based on GO annotation of Nur77-regulated genes in Min6 cells (Fig. 3B).