Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders such as obesity, metabolic syndrome and type 2 diabetes. Several studies have shown that expression of Steap4 is modulated by inflammatory cytokines, hormones and other indicators of cellular stress and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4's role in metal homeostasis is critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of STEAP4 with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure and function as it relates to metabolic diseases. We then examine how STEAP4's role as a regulator of cellular iron and copper may relate to type 2 diabetes.
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