Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

Ohashi, Wakana; Kimura, Shunsuke; Iwanaga, Toshihiko; Furusawa, Yukihiro; Irié, Tarou; Izumi, Hironori; Watanabe, Takashi; Hijikata, Atsushi; Hara, Takafumi; Ohara, Osamu; Koseki, Haruhiko; Sato, Toshiro; Robine, Sylvie; Mori, Hisashi; Hattori, Yoshiyuki; Watarai, Hiroshi; Mishima, Kenji; Ohno, Hiroshi; Hase, Koji; Fukada, Toshiyuki

doi:10.1371/journal.pgen.1006349

Cited by 82 publications

(93 citation statements)

References 51 publications

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“…The +4 cells are thought to be quiescent cells, whereas CBC cells are actively cycling and are marked by Lgr5 or Olfm4 [17] . We also found that ZIP7 is expressed in active cycling Olfm4 + stem cells indicating that ZIP7 may have an important role in the intestinal self-renewal process [14] .…”

Section: Zip7 Is Expressed In the Intestinal Crypt Where The Intestinmentioning

confidence: 55%

“…We found that ZIP7 was highly expressed in the crypt epithelium than in the villus epithelium [14] . Intestinal crypts are the region where intestinal stem cells are self-renewed and generate TA cells.…”

Section: Zip7 Is Expressed In the Intestinal Crypt Where The Intestinmentioning

confidence: 75%

“…Although in mammals, ZIP7 is ubiquitously expressed in the adult tissues, physiological in vivo functions of ZIP7 have remained unknown. In the next part, we have described the roles of zinc homeostasis in intestinal regulation, by mainly focusing on the zinc transporter ZIP7 [14] .…”

Section: Research Highlightmentioning

confidence: 99%

“…Thus, the intestinal crypts are highly proliferative compartments and are responsible for providing vigorous epithelial cell turnover and maintenance of the stem cells (Figure 2). We found that ZIP7 was highly expressed in this region, and therefore we investigated the roles of ZIP7 in the maintenance of intestinal epithelial homeostasis, as described below [14] .…”

Section: Regulation Of Intestinal Epithelium By Zinc Homeostasismentioning

confidence: 99%

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Emerging role of zinc homeostasis by zinc transporter ZIP7 in intestinal homeostatic self-renewal

2017

Inflamm Cell Signal

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There has been a growing interest in the biological significance of zinc and its regulatory mechanism in the development of tissue and in the maintenance of tissue homeostasis. The intestinal epithelium undergoes a continuous self-renewing process to maintain the intestinal homeostasis. Moreover, dysregulation of this process often causes various intestinal disorders including inflammatory bowel disease, ulcer, and cancer. However, the molecular basis of zinc-dependent regulation of intestinal epithelial cell turnover is not fully understood. In this research highlight, we describe that the zinc transporter ZIP7 (highly expressed in undifferentiated epithelial cells) plays a critical role in the intestinal epithelial self-renewal process by alleviating the ER stress during vigorous proliferative response. Our findings also provide evidence showing that the fine-tuning of intracellular zinc homeostasis by ZIP7 is essential to maintain epithelial homeostasis in the intestine.

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Section: Zip7 Is Expressed In the Intestinal Crypt Where The Intestinmentioning

confidence: 55%

Section: Zip7 Is Expressed In the Intestinal Crypt Where The Intestinmentioning

confidence: 75%

Section: Research Highlightmentioning

confidence: 99%

Section: Regulation Of Intestinal Epithelium By Zinc Homeostasismentioning

confidence: 99%

See 2 more Smart Citations

Emerging role of zinc homeostasis by zinc transporter ZIP7 in intestinal homeostatic self-renewal

2017

Inflamm Cell Signal

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“…In addition, ZnT5 −/− / ZnT7 −/− cells displayed an exacerbated ER stress response (26). Similarly, KD of Zip7, Zip13, and ZnT3 in cells induced ER stress and higher cell death, indicating the importance of normal zinc homeostasis for ER stress adaptation (27,28,60).…”

Section: Discussionmentioning

confidence: 98%

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

Kim

Aydemir

Kim

et al. 2017

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

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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

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Zinc Transport in the Mammalian Intestine

Hennigar

McClung

2018

Comprehensive Physiology

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Zinc homeostasis is primarily maintained in the proximal small intestine. Sophisticated transport mechanisms maintain zinc homeostasis by controlling the uptake and efflux of zinc in intestinal absorptive epithelial cells. Zrt‐irt‐like proteins (ZIPs) and zinc transporters (ZnTs) function in a coordinated manner to assimilate zinc from the lumen of the small intestine, subcellular compartments within the absorptive epithelial cell, and circulation. This manuscript details zinc transport mechanisms in the mammalian small intestine, along with factors that regulate these processes and consequences of dysregulated zinc transport. © 2019 American Physiological Society. Compr Physiol 9:59‐74, 2019.

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Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

Cited by 82 publications

References 51 publications

Emerging role of zinc homeostasis by zinc transporter ZIP7 in intestinal homeostatic self-renewal

Emerging role of zinc homeostasis by zinc transporter ZIP7 in intestinal homeostatic self-renewal

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

Zinc Transport in the Mammalian Intestine

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