Zinc transporter ZIP14 (SLC39A14) is a member of the SLC39A family of zinc transporters. However, in addition to zinc, SLC39A14 has also been shown to transport cadmium and manganese, as well as transferrin-bound and non-transferrin-bound iron (NTBI). However, the transport roles of SLC39A14 for zinc are primary while for NTBI and manganese are secondary. Analyses of ZIP14 secondary structure prediction showed that it has 8 transmembrane domains, a long extracellular N-terminus, a short extracellular C-terminus, and numerous histidine-rich repeats. The expression of SLC39A14 was documented to be mainly in the liver, intestine, brain, adipose, and bone. SLC39A14-mediated zinc transport influences cell signaling related to cell proliferation, apoptosis prevention, and suppression of inflammatory pathways.
|Basic Information of SLC39A14|
|Protein Name||Zinc transporter ZIP14|
|Aliases||LIV-1 subfamily of ZIP zinc transporter 4, Solute carrier family 39 member 14, Zrt- and Irt-like protein 14, ZIP14|
|Organism||Homo sapiens (Human)|
Studies of the SLC39A14 knockout mice reveal multiple functions of SLC39A14 in the liver, adipose tissue, brain, pancreas, and bone. Firstly, SLC39A14 is involved in inflammation and is identified as a gene responsive to the main proinflammatory cytokine of the acute-phase genes, IL-6. Besides, SLC39A14 localizes to the plasma membrane of hepatocytes and contributes to hypozincemia in the liver, which is a classic acute-phase response. Moreover, SLC39A14 might play a role in adipocyte differentiation and inflammatory obesity. Secondly, a prominent feature of the SLC39A14 ablation is a reduction in intestinal barrier function and onset of metabolic endotoxemia. Thirdly, SLC39A14 ablation in mice produces a defect in manganese excretion that leads to excess manganese accumulation in the brain that produces characteristics of Parkinson’s disease. Besides, studies have also reported the role of SLC39A14 in bone homeostasis regulation and cancer-induced muscle wasting.
Fig.1 Predicted model of SLC39A14 topology.
Using the Zip14 knockout mice, this study investigated the role of ZIP14 protein in the regulation of endosomal insulin receptor activity and glucose homeostasis in hepatocytes. The results indicated that modulation of this transporter might be a novel target for the management of diabetes and other glucose-related disorders.
Using the Zip14 knockout mice, this study investigated the role of ZIP14 in the regulation of bone homeostasis. The results showed that ablation of this gene led to decreased bone mass.
Using the Zip14 knockout mice, this study investigated the role of the ZIP14-mediated hepatic zinc uptake in adaption to endoplasmic reticulum (ER) stress. The results suggested an important role of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.
Using Zip14 knockout mice, the study investigated the role of ZIP14 in manganese homeostasis. Comparative metabolic, imaging and functional studies were conducted, and the results showed that the deletion of Zip14 gene led to increased manganese deposition, neurotoxic signatures, and diminished motor activity, which was signs of neurological diseases.
In this study, the ZIP14 protein was identified as a critical mediator of cancer-induced cachexia and that ZIP14 might be tested as a therapeutic target for the treatment of metastatic cancer-induced muscle wasting.
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