Abstract
Zinc influences signaling pathways through controlled targeted zinc transport. Zinc transporter Zip14 KO mice display a phenotype that includes impaired intestinal barrier function with low grade chronic inflammation, hyperinsulinemia, and increased body fat, which are signatures of diet-induced diabetes (type 2 diabetes) and obesity in humans. Hyperglycemia in type 2 diabetes and obesity is caused by insulin resistance. Insulin resistance results in inhibition of glucose uptake by liver and other peripheral tissues, principally adipose and muscle and with concurrently higher hepatic glucose production. Therefore, modulation of hepatic glucose metabolism is an important target for antidiabetic treatment approaches. We demonstrate that during glucose uptake, cell surface abundance of zinc transporter ZIP14 and mediated zinc transport increases. Zinc is distributed to multiple sites in hepatocytes through sequential translocation of ZIP14 from plasma membrane to early and late endosomes. Endosomes from Zip14 KO mice were zinc-deficient because activities of the zinc-dependent insulin-degrading proteases insulin-degrading enzyme and cathepsin D were impaired; hence insulin receptor activity increased. Transient increases in cytosolic zinc levels are concurrent with glucose uptake and suppression of glycogen synthesis. In contrast, Zip14 KO mice exhibited greater hepatic glycogen synthesis and impaired gluconeogenesis and glycolysis related to low cytosolic zinc levels. We can conclude that ZIP14-mediated zinc transport contributes to regulation of endosomal insulin receptor activity and glucose homeostasis in hepatocytes. Therefore, modulation of ZIP14 transport activity presents a new target for management of diabetes and other glucose-related disorders.
Highlights
Zinc influences signaling pathways through controlled targeted zinc transport
Ablation of Zip14 Prevents Hepatic Insulin Resistance—It has been shown in mice, pigs, and humans that a high fat diet (HFD)2 increases blood endotoxin levels leading to metabolic
This indicates that with the Zip14 KO mice, we successfully modeled metabolic endotoxemia that is induced by a high fat dietary intervention
Summary
Zinc transporter Zip KO mice display a phenotype that includes impaired intestinal barrier function with low grade chronic inflammation, hyperinsulinemia, and increased body fat, which are signatures of diet-induced diabetes (type 2 diabetes) and obesity in humans. We can conclude that ZIP14-mediated zinc transport contributes to regulation of endosomal insulin receptor activity and glucose homeostasis in hepatocytes. In keeping with these characteristics, Zip KO mice display impaired intestinal barrier function [24] with low grade chronic inflammation signatures They precipitate the development of insulin resistance in adipose tissue from Zip KO mice [25]. Our novel finding that both hepatic zinc and glucose homeostasis are altered when zinc transporter Zip is deleted provides a suitable in vivo model for detailed mechanistic studies. We conducted experiments using the Zip KO mouse model to evaluate a potential mechanism where zinc transport mediated by ZIP14 is involved in hepatic glucose metabolism
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