Transcriptional stimulation of TXNIP mRNA in response to increased glucose has been previously studied (Cha-Molstad et al., 2009; Yu and Luo, 2009). In response to elevated glucose levels, the transcription factor carbohydrate response element-binding protein (ChREBP) interacts with a consensus element in the TXNIP promoter to increase TXNIP transcription (Yu and Luo, 2009). We noted that ChREBP translocates to the nucleus, and binds TXNIP promoter elements under ER stress (Figure S5A and B). Furthermore, under ER stress, ChREBP mRNA itself increases about two-fold (Figure S5C). Luciferase reporter constructs containing variable TXNIP promoter regions, including two carbohydrate response elements (ChoREs) are activated in response to ER stress; but activation of the reporter constructs was never greater than about two-fold, in contrast to the robust induction that occurs under hyperglycemia (Figure S5D–F). Thus, while some contribution of de novo TXNIP transcription can be traced to known cis (ChORE) and trans (ChREBP) elements (Figure S5G–I), transcriptional activation is significantly weaker than under hyperglycemia, and hence insufficient to account for the robust increases in TXNIP mRNA to their new steady-states under ER stress. This
