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Physiological role of intestinal copper transporter ATP7A in iron metabolism

Başlık çevirisi mevcut değil.

  1. Tez No: 400828
  2. Yazar: ŞÜKRÜ GÜLEÇ
  3. Danışmanlar: DR. JAMES F. COLLINS
  4. Tez Türü: Doktora
  5. Konular: Beslenme ve Diyetetik, Nutrition and Dietetics
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2013
  8. Dil: İngilizce
  9. Üniversite: University of Florida
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 106

Özet

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Özet (Çeviri)

The Menkes Copper-Transporting ATPase (Atp7a) is an intestinal copper (Cu) transporter that is essential for assimilation of dietary Cu. Studies showed that Atp7a is induced in the rodent intestine during iron (Fe) deficiency, when serum and liver Cu levels increase. Thus, to test the hypothesis that Atp7a is important for Fe absorption and maintain Fe balance in body during Fe deficiency, I initiated an investigation in Atp7a mutant (Brindled) male mice. Brindled mice express mutant form of Atp7a with reduced function. Because mutant mice die perinatally of severe Cu deficiency, Cu was administered intraperitoneally at 7 and 9 days-of-age. After 3 month recovery period, rescued mutant mice and wild-type littermates were deprived of dietary Fe for 3 weeks, and Fe homeostasis was studied. Results showed that Brindled mice were able to appropriately regulate Fe absorption in response to Fe deprivation; however, unlike the situation in wild-type littermates, subsequent changes in intestinal and liver Cu levels in the mutants may have been necessary to support Fe homeostasis. An essential role for Atp7a in Fe absorption in these mice was thus not clearly identified, but possible residual Atp7a function and the complex Fe - and Cu -deficient phenotype of the mutant mice complicated data interpretation. Next, I evaluated a possible role for Atp7a in Fe absorption by developing Atp7a knock down (KD) rat intestinal epithelial (IEC-6) cells using shRNA technology. In Atp7a KD cells, Cu loading increased intracellular Cu levels, consistent with defective Cu export function of Atp7a. Expression of Fe transport-related genes was altered in KD cells. Expression of hephaestin (Heph), ferroxidase important for Fe export from intestine, was strongly repressed in KD cells. Heph downregulation was associated with a reduction in ferroxidase activity in KD cells. Conversely, expression of ferroportin 1 (Fpn1), basolateral Fe exporter, increased in KD cells. Importantly, increased Fpn1 expression correlated with enhanced transepithelial Fe transport observed in the Atp7a KD cells. This increase in transport suggested a minimal role for Heph in Fe absorption. Atp7a silencing thus altered Fe flux, suggesting that Atp7a function or intracellular Cu levels are important to maintain cellular Fe homeostasis.

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