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Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα-dependent manner.

FASEB J. 2019 Mar;33(3):3549-3561. doi:10.1096/fj.201801855R. Epub 2018 Nov 13
Luqing Zhao 1 , Thomas Bartnikas 2 , Xiangpeng Chu 3 , Janet Klein 4 , Chris Yun 5 , Shanthi Srinivasan 5 , Peijian He 1
Luqing Zhao 1 , Thomas Bartnikas 2 , Xiangpeng Chu 3 , Janet Klein 4 , Chris Yun 5 , Shanthi Srinivasan 5 , Peijian He 1
+ et al

[No authors listed]

Author information
  • 1 Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 2 Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA.
  • 3 Department of Thoracic Surgery, People's Hospital of Rizhao, Shandong, China.
  • 4 Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; and.
  • 5 Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA.

摘要


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. mediates many diabetic complications, and activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with duanyu1531α deficiency did not show increases in iron uptake and BBM DMT1 expression. High-glucose treatment increased plasma membrane DMT1 expression via the activation of duanyu1531α in cultured IECs. Inhibition of duanyu1531α potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that duanyu1531α 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 manner.

KEYWORDS: HIF2α ubiquitination, diabetes, iron uptake