The metabolic function of the metal transporter SLC39A14

Microelement is one of the nutritional elements of the human body. They participate in a wide range of physiological and biochemical functions of the human body, such as electron transport, oxygen delivery, enzyme activity, and cell growth and differentiation, etc. They also could be used as auxiliary components of biological macromolecules, or as the functional components of hormones and vitamins, which are of great significance to maintain life activities. Among them, essential trace elements, such as iron, zinc, and manganese, are not produced or synthesized in the body, but indispensable to maintain the whole-body physiological function. Essential trace elements are absorbed and transported into the blood circulation by a variety of metal transporters in the upper digest tract. Recently, with the identification and discovery of metal transporters and multifunctional study, we gain an in-depth understanding of metal transporters in metabolic organs and various metabolic diseases. Solute carrier 39 (SLC39), also known as zinc importer protein (ZIP) family, is a metal importer. According to the homology analysis of gene sequence, this family has 14 members, SLC39A1–SLC39A14 (ZIP1–ZIP14). Based on the protein structure, ZIP family could be divided into four subfamilies: I, II, Gufa, and LIV-1. SLC39A14 belongs to the LIV-1 subfamily of ZIP zinc transporters (LZT) family. It has 8 transmembrane domains (TM), histidine-rich domains and a conserved “HEXHEXGD” fragment. SLC39A14 is mainly expressed on the cellular membrane. Recent studies have demonstrated that it is involved in the absorption of metals like zinc, iron, and manganese in different metabolic tissues or organs. The function of SLC39A14 was investigated by generating global or tissue-specific knockout mice in different metabolic organs such as the liver, pancreas, adipose, and skeletal muscle. Most of these studies indicate that Slc39a14 -deletion may perturb tissue metabolic functions, such as insulin synthesis and secretion, disrupted insulin sensitivity or tissue metal absorption. More specifically, for the Slc39a14 global knockout mice ( Slc39a14-KO ), the insulin sensitivity and adipocyte differentiation are impaired in adipose tissue. Slc39a14-KO also disrupts gluconeogenesis in hepatic tissue induced by low tissue zinc content. Meanwhile, hepatocyte-specific knockout of Slc39a14 shows that SLC39A14 may be involved in hepatic manganese transportation and non-transferrin-bound iron (NTBI). In the mouse β cell line (Min6), SLC39A14 is involved in the endocrinal function of the pancreas, especially the insulin synthesis and secretion function in β cell. Furthermore, SLC39A14 function in skeletal muscle and myoblast suggests that SLC39A14 may regulate tissue zinc homeostasis in skeletal muscle of tumor metastasis animal model. In C2C12 myoblasts, SLC39A14 participates in myogenic differentiation and myotube development. In addition, the expression of SLC39A14 is not only regulated by the concentration of trace elements in blood circulation and intake level of elements from diets but also regulated by inflammatory factors such as LPS and IL-6. In this review, the metabolic function of metal transporters SLC39A14 in different tissues and organs is summarized.