Hepatokine Selenoprotein P-Mediated Reductive Stress Causes Resistance to Intracellular Signal Transduction.

Selenoprotein P functions as a redox protein through its intrinsic thioredoxin domain and by distributing selenium to intracellular glutathione peroxidases, that is, glutathione peroxidase 1 and 4. : Selenoprotein P was rediscovered as a hepatokine that causes the pathology of type 2 diabetes and aging-related diseases, including exercise resistance in the skeletal muscle, insulin secretory failure in pancreatic β cells, angiogenesis resistance in vascular endothelial cells, and myocardial ischemicreperfusion injury. It was unexpected for the antioxidant selenoprotein P to cause insulin resistance, because oxidative stress associated with obesity and fatty liver is a causal factor for hepatic insulin resistance. : Oxidative stress induced by the accumulation of reactive oxygen species (ROS) has a causal role in the development of insulin resistance, whereas ROS themselves function as intracellular second messengers that promote insulin signal transduction. ROS act both positively and negatively in insulin signaling depending on their concentrations. It might be possible that selenoprotein P causes "reductive stress" by eliminating a physiological ROS burst that is required for insulin signal transduction, thereby causing insulin resistance. In a large-scale intervention study, selenium supplementation that upregulates selenoprotein P was paradoxically associated with an increased risk for diabetes in humans. This review discusses the molecular mechanisms underlying the selenoprotein P-mediated resistance to angiogenesis and to exercise. : Selenoprotein P may be the first identified intrinsic factor that induces reductive stress, causing resistance to intracellular signal transduction, which may be the therapeutic target against sedentary-lifestyle-associated diseases, such as diabetes and obesity.