The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker?

Abstract

Mammalian thioredoxin reductase (TrxR) is a selenoprotein with three existing isoenzymes (TrxR1, TrxR2, and TrxR3), which is found primarily intracellularly but also in extracellular fluids. The main substrate thioredoxin (Trx) is similarly found (as Trx1 and Trx2) in various intracellular compartments, in blood plasma, and is the cell's major disulfide reductase. Thioredoxin reductase is necessary as a NADPH-dependent reducing agent in biochemical reactions involving Trx. Genetic and environmental factors like selenium status influence the activity of TrxR. Research shows that the Trx/TrxR system plays a significant role in the physiology of the adipose tissue, in carbohydrate metabolism, insulin production and sensitivity, blood pressure regulation, inflammation, chemotactic activity of macrophages, and atherogenesis. Based on recent research, it has been reported that the modulation of the Trx/TrxR system may be considered as a new target in the management of the metabolic syndrome, insulin resistance, and type 2 diabetes, as well as in the treatment of hypertension and atherosclerosis. In this review evidence about a possible role of this system as a marker of the metabolic syndrome is reported.

Keywords: Diabetes; Obesity; Selenium; Thioredoxin interacting protein; Thioredoxin reductase.

Fig. 1

Reaction sequence of TrxR-mediated reduction of protein disulfides

Fig. 2

The mechanistic scheme of the effect of interaction between Trx and TXNIP signaling on adipose tissue development and functioning. Normal Trx redox cycling is required for adipogenesis, whereas increased TXNIP levels appear to inhibit differentiation and maturation of adipocytes. At the same time, TXNIP signaling is associated with adipose tissue dysfunction, leading to obesity and metabolic syndrome. The dotted line is indicative of the level of Trx that seem to be increased in the early stages of adipocyte hypertrophy as a compensatory response to oxidative stress. At further stages, increased TXNIP levels, as well as increased oxidative stress and Trx requirements, result in a decrease in Trx levels

Fig. 3

The proposed effect of the balance between Trx and TXNIP effects on metabolic syndrome and its components through modulation of oxidative stress, inflammatory response (as general mechanisms of pathogenesis), and specific mechanisms of tissue dysfunction