Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner
Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner
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DOI：
10.1096/fj.201801855r
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发表时间：
2018-11
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通讯作者：
Luqing Zhao;T. Bartnikas;Xiangpeng Chu;J. Klein;C. Yun;S. Srinivasan;Peijian He
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文献类型：
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作者：
Luqing Zhao;T. Bartnikas;Xiangpeng Chu;J. Klein;C. Yun;S. Srinivasan;Peijian He
过量的铁会增加糖尿病和糖尿病并发症的发病率。反过来，糖尿病诱导铁负荷，根据最近的报告，部分归因于肠铁输出升高。在此，我们发现，铁摄取和铁进口二价金属转运蛋白1（DMT 1）的mRNA表达显着增加，在十二指肠链脲佐菌素诱导的糖尿病小鼠。免疫荧光染色显示，人类肠道活检刷状缘膜（BBM）的增加和减少细胞质DMT 1的表达在糖尿病患者，这表明易位的DMT 1。糖尿病小鼠的免疫印迹结果证实了这种DMT 1调节模式，显示BBM DMT 1表达增加了210%，而总DMT 1增加了60%。PKC介导多种糖尿病并发症，糖尿病小鼠肠道PKCα活性增高。有趣的是，PKCα缺乏的糖尿病小鼠没有表现出铁摄取和BBM DMT 1表达的增加。高糖处理通过激活培养的IEC中的PKCα增加质膜DMT 1表达。抑制PKCv可增强DMT 1蛋白的泛素化和降解。我们进一步表明，高糖抑制膜DMT 1内化。这些发现表明，PKCα促进微绒毛膜DMT 1表达和肠铁摄取，有助于糖尿病铁负荷。赵，L.，Bartnikas，T.，Chu，X.，克莱因，J.，Yun，C.，Srinivasan，S.，He，P. Hyperglycemia以PKCα依赖的方式促进肠上皮细胞中DMT 1的微绒毛膜表达。FASEB J. 33，3549-3561（2019）。www.fasebj.org
Excessive iron increases the incidence of diabetes and worsens diabetic complications. Reciprocally, diabetes induces iron loading, partially attributable to elevated intestinal iron export according to a recent report. Herein, we show that iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were significantly increased in the duodenum of streptozotocin‐induced diabetic mice. Immunofluorescence staining of human intestinal biopsies revealed increased brush border membrane (BBM) and decreased cytoplasmic DMT1 expression in patients with diabetes, suggesting translocation of DMT1. This pattern of DMT1 regulation was corroborated by immunoblotting results in diabetic mice showing that BBM DMT1 expression was increased by 210%, in contrast to a 60% increase in total DMT1. PKC mediates many diabetic complications, and PKCα activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with PKCα deficiency did not show increases in iron uptake and BBM DMT1 expression. High‐glucose treatment increased plasma membrane DMT1 expression via the activation of PKCα in cultured IECs. Inhibition of PKCv potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that PKCα promotes microvillus membrane DMT1 expression and intestinal iron uptake, contributing to diabetic iron loading.—Zhao, L., Bartnikas, T., Chu, X., Klein, J., Yun, C., Srinivasan, S., He, P. Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner. FASEB J. 33, 3549–3561 (2019). www.fasebj.org