title: Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia).
abstract: ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn(2+) and non-transferrin-bound Fe(2+) in vitro. Using a Zip14(-/-) mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14(-/-) mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14(-/-) mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14-/- mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14(-/-) phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14(-/-) mice and their phenotype shows defects in glucose homeostasis.
authors.affiliation: Food Science and Human Nutrition Department and Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL, USA.
authors.forename: Tolunay Beker
authors.initials: TB
authors.lastname: Aydemir
authors.forename: Shou-Mei
authors.initials: SM
authors.lastname: Chang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Guthrie
authors.forename: Alyssa B
authors.initials: AB
authors.lastname: Maki
authors.forename: Moon-Suhn
authors.initials: MS
authors.lastname: Ryu
authors.forename: Afife
authors.initials: A
authors.lastname: Karabiyik
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cousins
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C497524:SLC39A14 protein, human; D007501:Iron; D005947:Glucose; D015032:Zinc