Role of zinc in health and disease

Abstract

This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.

Keywords: Acrodermatitis enteropathica; ZIP; Zinc; Zinc deficiency; Zinc toxicity; ZnT.

Fig. 1

Zinc uptake under physiological conditions. Zinc ions are transported from the intestinal lumen into the enterocyte by ZIP4. Other zinc transporters on the apical membrane include ZIP8 [101], ZnT10 [67] and ZnT5B [56]. ZnT5B has a bidirectional transport function [56]. Transporters located on the basolateral membrane of the enterocyte include ZnT1 [44], ZIP14 [102] and ZIP5 [103]. ZnT1 transports zinc ions from the enterocyte into the portal vein. Zinc ions travel in the portal blood to the liver, most likely bound to citrate, amino acids [96] and transferrin [97]. At the liver, portal blood drains through sinusoids, from where some zinc is taken up by hepatocytes. The rest of the zinc joins the systemic circulation from where it can reach distant tissues such as the brain, muscle, and bone via their respective ZIP transporters. Figure created with BioRender.com

Fig. 2

Mechanisms/events underlying zinc deficiency due to mutation in ZIP4 (Acrodermatitis enteropathica). In acrodermatitis enteropathica, there is a mutation in the SLC39A4 gene which encodes the ZIP4 protein. Dysfunctionality in ZIP4 transporter causes limited zinc uptake by the enterocyte, and therefore, insufficient zinc transported into the portal vein via ZnT1. Insufficient zinc ions enter the liver and the systemic circulation, leading to less zinc reaching other tissues. The result is zinc deficiency, which can be life-threatening, if not treated promptly. Figure created with BioRender.com