Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Troche

Journal of Biological Chemistry

et al. 2016

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Edited by Jeffrey PessinZinc 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.

Section: Discussioncontrasting

confidence: 79%

mentioning

confidence: 99%

Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin Receptor Trafficking and Glucose Metabolism

Troche

Journal of Biological Chemistry

et al. 2016

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“…Serum was diluted 1:5 in Milli-Q® water for AAS. Tissues were weighed and digested in HNO 3 (90°C for 3 hours) and diluted (1:1 to 1:5) with Milli-Q® water for AAS (Troche et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

“…The regulation of Zip14 by IL-6 suggests ZIP14 expression could be influenced by aging. Mice with a knockout (KO) of Zip14 have a phenotype that includes metabolic endotoxemia and altered glucose regulation (Aydemir et al, 2012; Guthrie et al, 2015; Troche et al, 2016). Such phenotypes are associated with aging.…”

Section: Introductionmentioning

confidence: 99%

Aging amplifies multiple phenotypic defects in mice with zinc transporter Zip14 (Slc39a14) deletion

Troche

Experimental Gerontology

et al. 2016

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Inflammation and zinc dyshomeostasis are two common hallmarks of aging. A major zinc transporter ZIP14 (slc39a14) is upregulated by proinflammatory stimuli, e.g. interleukin-6. We have evaluated the influence of age on the Zip14 KO phenotype using wild-type (WT) and Zip14 knockout (KO) mice. Aging produced a major increase in serum IL-6 concentrations that was dramatically augmented in the Zip14 KO mice. In keeping with enhanced serum IL-6 concentrations, aging produced tissue-specific increases in zinc concentration of skeletal muscle and white adipose tissue. Metabolic endotoxemia produced by Zip14 ablation is maintained in aged KO mice. Muscle non-heme iron (NHI) was increased in aged WT mice but not in aged Zip14 KO mice demonstrating NHI uptake by muscle is ZIP14-dependent and increases with age. NF-κB and STAT3 activation was greater in aged mice, but was tissue specific and inversely related to tissue zinc. Micro-CT analysis revealed that Zip14 KO mice had markedly reduced trabecular bone that was greatly amplified with aging. These results demonstrate that the inflammation-responsive zinc transporter ZIP14 has phenotypic effects that are amplified with aging.

“…Ablation of some of these transporters results in zinc dyshomeostasis and metabolic defects. Ablation of Zip14 (Slc39a14) in mice leads to a phenotype that includes endotoxemia, hyperinsulinemia, increased body fat, and impaired hepatic insulin receptor trafficking (19)(20)(21). Zinc and zinc transporters have been implicated in ER stress and the UPR.…”

mentioning

confidence: 99%

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Proc. Natl. Acad. Sci. U.S.A.

et al. 2017

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Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 −/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.unfolded protein response | p-eIF2α/ATF4/CHOP pathway | apoptosis | steatosis | zinc metabolism