Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models.

Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear. Considering that several ectoenzymes involved in purinergic signaling through extracellular adenine-nucleotide hydrolysis possess zinc ions in their active sites, and disorders in purinergic signaling result in diverse diseases that are frequently similar to those caused by zinc deficiency, herein we examine whether zinc deficiency affects extracellular adenine-nucleotide metabolism. Zinc deficiency severely impairs the activities of major ectoenzymes (ENPP1, ENPP3, NT5E/CD73, and TNAP), and also strongly suppresses adenine-nucleotide hydrolysis in cell-membrane preparations or rat plasma, thereby increasing ATP and ADP levels and decreasing adenosine levels. Thus, zinc deficiency delays both extracellular ATP clearance and adenosine generation, and zinc modulates extracellular adenine-nucleotide metabolism. Since the finely tuned balance between extracellular adenine nucleotides and adenosine is critical for purinergic signaling, these findings provide a novel insight into why zinc deficiency results in diverse symptoms.

Properties of Zip4 accumulation during zinc deficiency and its usefulness to evaluate zinc status: a study of the effects of zinc deficiency during lactation.

Systemic and cellular zinc homeostasis is elaborately controlled by ZIP and ZnT zinc transporters. Therefore, detailed characterization of their expression properties is of importance. Of these transporter proteins, Zip4 functions as the primarily important transporter to control systemic zinc homeostasis because of its indispensable function of zinc absorption in the small intestine. In this study, we closely investigated Zip4 protein accumulation in the rat small intestine in response to zinc status using an anti-Zip4 monoclonal antibody that we generated and contrasted this with the zinc-responsive activity of the membrane-bound alkaline phosphatase (ALP). We found that Zip4 accumulation is more rapid in response to zinc deficiency than previously thought. Accumulation increased in the jejunum as early as 1 day following a zinc-deficient diet. In the small intestine, Zip4 protein expression was higher in the jejunum than in the duodenum and was accompanied by reduction of ALP activity, suggesting that the jejunum can become zinc deficient more easily. Furthermore, by monitoring Zip4 accumulation levels and ALP activity in the duodenum and jejunum, we reasserted that zinc deficiency during lactation may transiently alter plasma glucose levels in the offspring in a sex-specific manner, without affecting homeostatic control of zinc metabolism. This confirms that zinc nutrition during lactation is extremely important for the health of the offspring. These results reveal that rapid Zip4 accumulation provides a significant conceptual advance in understanding the molecular basis of systemic zinc homeostatic control, and that properties of Zip4 protein accumulation are useful to evaluate zinc status closely.

Overview of Inherited Zinc Deficiency in Infants and Children.

Zinc nutrition is of special practical importance in infants and children. Poor zinc absorption causes zinc deficiency, which leads to a broad range of consequences such as alopecia, diarrhea, skin lesions, taste disorders, loss of appetite, impaired immune function and neuropsychiatric changes and growth retardation, thus potentially threatening life in infants and children. In addition to dietary zinc deficiency, inherited zinc deficiency, which rarely occurs, is found during the infant stage and early childhood. Recent molecular genetic studies have identified responsible genes for two inherited zinc deficiency disorders, acrodermatitis enteropathica (AE) and transient neonatal zinc deficiency (TNZD), clarifying the pathological mechanisms. Both of these zinc deficiencies are caused by mutations of zinc transporters, although the mechanisms are completely different. AE is an autosomal recessive disorder caused by mutations of the ZIP4 gene, consequently resulting in defective absorption of zinc in the small intestine. In contrast, TNZD is a disorder caused by mutations of the ZnT2 gene, which results in low zinc breast milk in the mother, consequently causing zinc deficiency in the breast-fed infant. In both cases, zinc deficiency symptoms are ameliorated by a daily oral zinc supplementation for the patients. Zinc is definitely one of the key factors for the healthy growth of infants and children, and thus zinc nutrition should receive much attention.