肠道微量元素代谢机制研究.pptxVIP

肠道铜铁微量元素代谢与调控谢黎炜 Ph.D.9.17.2016OutlineBackgroundQuestions from previous studies Three studies related to iron and copper absorption and homeostasis mechanisms Questions left and future studiesIronFe3+Fe2+Iron absorption, utilization and recycling 1-2 mg/dayAndrew, N.C.,2008 Systemic iron homeostasis iron deficiency iron overloadIron AbsorptionCeruloplasminMackenzie, M., et al. 2005Ferric iron reduced by DcytBImported by iron transporter Dmt1 on apical surface and exported by Ferroportin on basolateral sideFerrous iron oxidized by hephaestin or ceruloplasminDuring iron-deficiency, Dmt1 could transport some other metals such as copperCopper absorptionKim, B. et al. 2008Copper also absorbed via enterocytes of small intestine, localized to trans-Golgi and exported by Atp7aStored in liverSecreted through bileIron-deficiency and systemic copper homeostasisMicroarray of gene expression in iron-deficient rat duodenum Liver copper level in iron-deficient ratDmt1Atp7aCollins, J.F. et al. 2005 and Ravia, J.J., et al. 2005 Atp7a is a copper exporter located on basolateral side of small intestineAimCollins. J.F. et al. 2010 What are the regulatory mechanisms that induce Atp7a expression levels during iron-deficiency?What is the physiological importance of Atp7a during iron-deficiency?Potential mechanism mediated by iron-deprivationHIFHypoxiaHypoxia Inducible Factors (HIFs)Shah, Y. and Xie, L., 2013PublicationsXie, L. and Collins J.F. Am J Physiol Cell Physiol 300: C1298-1305, 2011.(IF:3.817)Xie, L. and J.F. CollinsAm J Physiol Cell Physiol, 2013 Feb 1;304(3):C257-62. (IF:3.817)Xie, L. and Collins, J.F. J Bio Chem, 2013 Aug 16;288(33):23943-52. (IF:4.573)Endogenous Atp7a up-regulated by hypoxia in IEC-6 cellsThree putitive HREs identified on Atp7a promoterOverexpression of HIF2α robustly increases Atp7a promoter activity224 bp Atp7a promoterHRE mutation reduced HIF2α-mediated inductionHIF binding site accompanied with GC-rich sequence-binding transcription factorAtp7a promoter