Figure 6.

Proposed model of TXNIP regulation by 1,25(OH)₂D₃ in HL-60 cells. 1,25(OH)₂D₃ appears to regulate TXNIP expression through multiple mechanisms depending on the duration of treatment (long and short term treatment outcomes are separated in the figure by a dashed line). In short term treatments, 1,25(OH)₂D₃ induces TXNIP mRNA, but not protein levels, an effect that depends on the availability of glucose. This points toward the possibility that the VDR physically/functionally interacts with the transcriptional heterodimer MondoA/MLX, for example, via enhancing its binding to ChoRE on the TXNIP promoter, or via facilitating its recruitment/nuclear translocation. Such putative interactions are depicted in the figure by a question mark. On the other hand, in long term treatments, 1,25(OH)₂D₃ induces TXNIP protein expression as well as intracellular ROS levels, effects that are also glucose-dependent. Furthermore, long term treatment with 1,25(OH)₂D₃ influences TXNIP stability possibly through multi-modal regulation of TXNIP-degrading machinery, for example the E3 ligase ITCH, different proteases, or proteasomal subunits. Whether the TXNIP gene harbors VDRE is unclear, thus the vitamin D receptor (VDR) is linked to TXNIP regulation via a dotted line. A blunted arrow (t-bar) indicates inhibitory activity.