title: Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.
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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Jim
authors.initials: J
authors.lastname: Geiser
authors.forename: Robert C
authors.initials: RC
authors.lastname: De Lisle
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Glen K
authors.initials: GK
authors.lastname: Andrews
mesh_terms: D000169:Acrodermatitis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D007464:Clioquinol / Q000819:agonists / Q000494:pharmacology*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015032:Zinc / Q000819:agonists / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D027682:Cation Transport Proteins; C477530:Slc39a4 protein, mouse; D007464:Clioquinol; D015032:Zinc