O ur understanding of how Zn is metabolized in animals and humans is advancing rapidly by examination of membrane proteins that facilitate Zn transport. Zn transporters fall into two gene families, SLC30A and SLC39A (1). These families are commonly referred to as ZnT and Zip transporters, respectively.Zn metabolism has been defined partially in studies with humans and animals by using radioactive and stable isotopes (reviewed in ref. 2). Kinetic analyses and metabolic modeling have established the major pathways by which this micronutrient is processed and how organ systems produce an effective homeostatic control over absorption and excretion. The current Dietary Reference Intake (Institute of Medicine of the National Academies,Washington, DC) recommendations for Zn intake by humans are based on a balance between intestinal absorption and endogenous losses by using these metabolic assessments (3).Dietary Zn restriction leads to an up-regulation of the mediated component of the Zn-absorptive pathway in rodents, presumably by means of changes programmed in intestinal cells (4). Loss of endogenous Zn from intestinal and pancreatic secretions are concomitantly reduced during Zn restriction (reviewed in refs. 5 and 6). Urinary losses of Zn are low, indicative of high reabsorptive capacity, and they are refractory to change over a wide Zn-intake range (6). Furthermore, metabolic studies have identified organ systems that influence Zn metabolism and its response to physiologic stimuli, including hormones, cytokines, and growth factors (reviewed in ref. 5). Induction of metallothionein (MT) gene expression, which is usually concurrent with enhanced cellular Zn acquisition, has been integrated into all of these aspects of cellular Zn trafficking.Zn transporters are essential components of systems that influence Zn trafficking in times of dietary depletion or excess, such as during acute and chronic physiologic stress (e.g., infection and inflammation) and during pregnancy and lactation. Therefore, experiments with mice were designed to show the differential expression of ZnT and Zip transporter genes associated with dietary Zn restriction and excess. The data presented here identify the transporters critical for regulation of Zn homeostasis in intestinal absorptive cells, as well as pancreatic acinar cells.
Materials and MethodsMice and Treatments. Young adult male CD-1 strain mice (Charles River Breeding Laboratories) were housed and fed as described in detail in refs. 7 and 8. Mice were fed one of three dietary Zn levels [Zn Ϫ (Ͻ1 mg͞kg), Zn normal (ZnN; 30 mg͞kg), or Zn ϩ (150 mg͞kg)], which represent depleted, adequate, or excessive intakes of Zn, respectively. Mice were fed individually for up to 21 days. Blood was collected by cardiac puncture under halothane anesthesia for measurement of the serum Zn concentration (7), and preparation of peripheral blood mononuclear cells (PBMCs) was performed by using NycoPrep 1.077 (Life Technologies, Grand Island, NY) gradient centrifugation. MT knockout mice and appropriate 1...