Searching for causality of knocking out Txnip: is Txnip missing in action?

Thioredoxin is an essential protein present in all known biological systems responsible for mediating the major pathway through which electrons are transferred from NADP(H) to protein disulfide bonds: NADP(H) R-S-SR 3NADP R-SH HS-R .1,2 Thus, the discovery that thioredoxin-interacting protein (Txnip) bound to and inhibited thioredoxin–NADPH–dependent reduction of protein disulfides3 predicted that Txnip would both counter thioredoxin-mediated protection from oxidative stress4–10 and have pleiotropic physiologic influence on process dependent on proteins containing disulfide determinants of structure/ function. Elegant quantitative trait loci positional cloning identifying Txnip as the gene responsible for the hyperlipidemia associated with the murine Hyplip1 locus clearly supported this prediction.11 In this issue of Circulation Research, Yoshioka et al12 describe how gene-targeted disruption of Txnip influences the response of mice to transverse aortic constriction (TAC) (ie, Txnip knockout mice displayed improved cardiac function 4 weeks after TAC but decreased cardiac function after 8 weeks). The findings that Txnip deletion caused no change in thioredoxin enzyme activity, whereas cardiac glucose uptake in Txnip knockout mice was increased led the authors to conclude that Txnip does not simply act via regulating redox state, but rather it acts as a novel metabolic regulator. This report provides several remarkably important insights regarding the function and targets of Txnip-thioredoxin.