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Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.

Geiser J, De Lisle RC, Finkelstein D, Adlard PA, Bush AI, Andrews GK - PLoS ONE (2013)

Bottom Line: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.In contrast, dietary CQ in conjunction with zinc supplementation was highly effective.These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.

ABSTRACT

Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.

Methods/principal findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 (intest KO) phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver.

Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

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ICP-MS quantification of essential metals in Zip4intest KO mice before and after feeding CQ/Zn.The small intestine, liver and pancreas from Zip4intest KO mice were harvested on d8 after initiation of the knockout and on d13 and d20 after starting CQ/Zn on d8 (3 to 5 mice per group). Only data that showed significant changes are presented. Concentrations (ppm) for liver zinc (A), iron (B), copper (C), manganese (D), and magnesium (E), and intestine iron (F), were normalize to sulfur concentrations (ppm). Individual tissue samples were analyzed by ICP-MS for multiple elements including these essential metals. Data are expressed as metal/sulfur ratio ± S.E.M. Statistical significance was determined using the Unpaired T-test (two-tailed). Values were considered different if P<0.05. *indicates P<0.05; **indicates P<0.01; ***indicates P<0.001. Our previous studies showed that iron, copper and manganese accumulate in the liver when Zip4 is knocked out in the intestine whereas iron is reduced in the intestine [26]. The symbol (>) on the Y-axes indicates approximate metal/sulfur ratios found in control mice.
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pone-0072543-g007: ICP-MS quantification of essential metals in Zip4intest KO mice before and after feeding CQ/Zn.The small intestine, liver and pancreas from Zip4intest KO mice were harvested on d8 after initiation of the knockout and on d13 and d20 after starting CQ/Zn on d8 (3 to 5 mice per group). Only data that showed significant changes are presented. Concentrations (ppm) for liver zinc (A), iron (B), copper (C), manganese (D), and magnesium (E), and intestine iron (F), were normalize to sulfur concentrations (ppm). Individual tissue samples were analyzed by ICP-MS for multiple elements including these essential metals. Data are expressed as metal/sulfur ratio ± S.E.M. Statistical significance was determined using the Unpaired T-test (two-tailed). Values were considered different if P<0.05. *indicates P<0.05; **indicates P<0.01; ***indicates P<0.001. Our previous studies showed that iron, copper and manganese accumulate in the liver when Zip4 is knocked out in the intestine whereas iron is reduced in the intestine [26]. The symbol (>) on the Y-axes indicates approximate metal/sulfur ratios found in control mice.

Mentions: Our previous studies of Zip4intest KO mice revealed that the homeostasis of several essential metals was progressively perturbed after initiation of the knockout. Elemental and essential metal analyses of small intestine, liver and pancreas showed that iron, manganese and copper accumulated to high levels by d8 in the liver [26]. Elemental and essential metal analyses were performed using inductively coupled plasma mass spectrometry (ICP-MS) of the above organs harvested from d8 Zip4intest KO mice and from d13 and d20 mice that had been provided dietary CQ/Zn (Fig. 7). Only changes that were statistically significant are shown and essential metal concentrations were normalized to sulfur concentrations as an internal control. Liver zinc increased after beginning the CQ/Zn diet, consistent with the concept that this ionophore is bringing zinc into the mice. Zinc levels were variable between individual mice but on d20, a statistically significant increase of zinc (28%) was noted in the liver (Fig. 7A). In contrast, decreased concentrations of iron (36%), copper (20%) and manganese (45%) in the liver were found (Fig. 7B-D). It was also noted that magnesium concentrations in the liver decreased 20% (Fig. 7E) by d13 and, in addition, manganese concentration in the pancreas transiently decreased (36%) on d13 but rebounded by d20 (data not shown). Our previous studies showed that the small intestine had lost ∼50% of its iron by d4 after the knockout was initiated [26]. Herein it was found that intestine iron increased 81% by d13 in mice provided the CQ/Zn diet and then declined (Fig. 7F). Taken together, these results suggest that the homeostasis of several essential metals is restored after providing extremely zinc deficient Zip4intest KO mice with dietary CQ/Zn.


Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.

Geiser J, De Lisle RC, Finkelstein D, Adlard PA, Bush AI, Andrews GK - PLoS ONE (2013)

ICP-MS quantification of essential metals in Zip4intest KO mice before and after feeding CQ/Zn.The small intestine, liver and pancreas from Zip4intest KO mice were harvested on d8 after initiation of the knockout and on d13 and d20 after starting CQ/Zn on d8 (3 to 5 mice per group). Only data that showed significant changes are presented. Concentrations (ppm) for liver zinc (A), iron (B), copper (C), manganese (D), and magnesium (E), and intestine iron (F), were normalize to sulfur concentrations (ppm). Individual tissue samples were analyzed by ICP-MS for multiple elements including these essential metals. Data are expressed as metal/sulfur ratio ± S.E.M. Statistical significance was determined using the Unpaired T-test (two-tailed). Values were considered different if P<0.05. *indicates P<0.05; **indicates P<0.01; ***indicates P<0.001. Our previous studies showed that iron, copper and manganese accumulate in the liver when Zip4 is knocked out in the intestine whereas iron is reduced in the intestine [26]. The symbol (>) on the Y-axes indicates approximate metal/sulfur ratios found in control mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3755987&req=5

pone-0072543-g007: ICP-MS quantification of essential metals in Zip4intest KO mice before and after feeding CQ/Zn.The small intestine, liver and pancreas from Zip4intest KO mice were harvested on d8 after initiation of the knockout and on d13 and d20 after starting CQ/Zn on d8 (3 to 5 mice per group). Only data that showed significant changes are presented. Concentrations (ppm) for liver zinc (A), iron (B), copper (C), manganese (D), and magnesium (E), and intestine iron (F), were normalize to sulfur concentrations (ppm). Individual tissue samples were analyzed by ICP-MS for multiple elements including these essential metals. Data are expressed as metal/sulfur ratio ± S.E.M. Statistical significance was determined using the Unpaired T-test (two-tailed). Values were considered different if P<0.05. *indicates P<0.05; **indicates P<0.01; ***indicates P<0.001. Our previous studies showed that iron, copper and manganese accumulate in the liver when Zip4 is knocked out in the intestine whereas iron is reduced in the intestine [26]. The symbol (>) on the Y-axes indicates approximate metal/sulfur ratios found in control mice.
Mentions: Our previous studies of Zip4intest KO mice revealed that the homeostasis of several essential metals was progressively perturbed after initiation of the knockout. Elemental and essential metal analyses of small intestine, liver and pancreas showed that iron, manganese and copper accumulated to high levels by d8 in the liver [26]. Elemental and essential metal analyses were performed using inductively coupled plasma mass spectrometry (ICP-MS) of the above organs harvested from d8 Zip4intest KO mice and from d13 and d20 mice that had been provided dietary CQ/Zn (Fig. 7). Only changes that were statistically significant are shown and essential metal concentrations were normalized to sulfur concentrations as an internal control. Liver zinc increased after beginning the CQ/Zn diet, consistent with the concept that this ionophore is bringing zinc into the mice. Zinc levels were variable between individual mice but on d20, a statistically significant increase of zinc (28%) was noted in the liver (Fig. 7A). In contrast, decreased concentrations of iron (36%), copper (20%) and manganese (45%) in the liver were found (Fig. 7B-D). It was also noted that magnesium concentrations in the liver decreased 20% (Fig. 7E) by d13 and, in addition, manganese concentration in the pancreas transiently decreased (36%) on d13 but rebounded by d20 (data not shown). Our previous studies showed that the small intestine had lost ∼50% of its iron by d4 after the knockout was initiated [26]. Herein it was found that intestine iron increased 81% by d13 in mice provided the CQ/Zn diet and then declined (Fig. 7F). Taken together, these results suggest that the homeostasis of several essential metals is restored after providing extremely zinc deficient Zip4intest KO mice with dietary CQ/Zn.

Bottom Line: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.In contrast, dietary CQ in conjunction with zinc supplementation was highly effective.These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.

ABSTRACT

Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.

Methods/principal findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 (intest KO) phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver.

Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

Show MeSH
Related in: MedlinePlus