title: Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin Receptor Trafficking and Glucose Metabolism.
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.
authors.affiliation: From the Food Science and Human Nutrition Department and Center for Nutritional Sciences College of Agricultural and Life Sciences and.
authors.forename: Tolunay Beker
authors.initials: TB
authors.lastname: Aydemir
authors.affiliation: From the Food Science and Human Nutrition Department and Center for Nutritional Sciences College of Agricultural and Life Sciences and.
authors.forename: Catalina
authors.initials: C
authors.lastname: Troche
authors.affiliation: From the Food Science and Human Nutrition Department and Center for Nutritional Sciences College of Agricultural and Life Sciences and.
authors.forename: Min-Hyun
authors.initials: MH
authors.lastname: Kim
authors.affiliation: From the Food Science and Human Nutrition Department and Center for Nutritional Sciences College of Agricultural and Life Sciences and cousins@ufl.edu.|the Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32611.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cousins
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport / Q000502:physiology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C500556:SLC39A14 protein, mouse; D006003:Glycogen; D011972:Receptor, Insulin; D005947:Glucose; D015032:Zinc
keywords: Insulin degrading enzyme; gluconeogenesis; glycogen; glycolysis; insulin; mitochondria