Regulation of Zinc Metabolism and Genomic Outcomes

Abstract

Differential mRNA display and cDNA array analysis have identified zinc-regulated genes in small intestine, thymus and monocytes. The vast majority of the transcriptome is not influenced by dietary zinc intake, high or low. Of the genes that are zinc regulated, most are involved in signal transduction (particularly influencing the immune response), responses to stress and redox, growth and energy utilization. Among the genes identified are uroguanylin (UG), cholecystokinin, lymphocyte-specific protein tyrosine kinase (LCK), T-cell cytokine receptor, heat shock proteins and the DNA damage repair and recombination protein-23B. Zinc transporters (ZnT) help regulate the supply of this micronutrient to maintain cellular functions. Expression of ZnT-1 and -2 is regulated by dietary zinc in many organs including small intestine and kidney. ZnT-4 is ubiquitously expressed but is refractory to zinc intake. Expression of ZnT-1, -2 and -4 changes markedly during gestation and lactation from highly abundant to undetectable. Each ZnT has an endosomal-like appearance in the tissues examined. Upregulation of ZnT-1 and ZnT-2 by dietary zinc strongly implicates these transporters in zinc acquisition and/or storage for subsequent systemic needs. THP-1 cells were used as a model to examine the response of human cells to changes in zinc status. Based on mRNA quantities, Zip1 and ZnT-5 were the most highly expressed. Zinc depletion of these cells decreased expression of all transporters except Zip2, where expression increased markedly. Collectively, these findings provide a genomic footprint upon which to address the biological and clinical significance of zinc and new avenues for status assessment.

Regulation and functional effects of ZNT8 in human pancreatic islets

“…Briefly, ZNT1 (SLC30A1) is ubiquitously expressed. It is the only transporter known to be involved in zinc efflux across the plasma membrane that confers resistance to zinc (Palmiter & Findley 1995, Liuzzi et al 2001, Cousins et al 2003. ZNT5 (SLC30A5) is expressed more abundantly in pancreatic b cells (Kambe et al 2002).…”

Determinants of serum zinc concentrations in a population of French middle-age subjects (SU.VI.MAX cohort)

“…Zinc is an essential component for the optimal function of a variety of biochemical and physiological processes (Hambidge, 2000;Cousins et al, 2003;Tudor et al, 2005). It is a major antioxidant trace element through zinc-induced metallothionein synthesis (Bell and Vallee, 2009), Zn-Cu superoxide dismutase, competition with iron and copper in Fenton's reaction and thiol group protection (Powell, 2000).…”

Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

“…This transmembrane protein has been investigated mainly in the context of zinc metabolism and has been shown to confer resistance to zinc toxicity (32)(33)(34)(35)(36). ZnT-1 is expressed in most tissues, with high levels of expression observed primarily in the brain, the pancreas, the testes, and the heart (37)(38)(39).…”