Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis Enteropathica

Abstract

BackgroundZinc 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 FindingsConditional 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.ConclusionsThese 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.

Metal chaperones prevent zinc-mediated cognitive decline

“…In whole animal studies, it has yet to be determined whether CQ is metallated when it enters the brain, but clearly these metal chaperones require the presence of zinc in order to have biological effect (Adlard et al, 2011;Crouch et al, 2011). Similarly, we also recently demonstrated that CQ and zinc alone were insufficient to rescue the phenotype present in a Zip4 intestinal KO model of acrodermatitis enteropathica, but the combination was highly effective (Geiser et al, 2013).…”

Zinc Homeostasis in Lung

“…ZIP4 Knockout (KO) mice embryos die during early development, whereas heterozygous mice exhibit a phenotype similar to AE secondary to impairment of intestinal absorption of zinc (Kury et al, 2002;Wang et al, 2002;Dufner-Beattie et al, 2007). Oral clioquinol and zinc supplementation can successfully rescue an AE phenotype in conditional ZIP4 KO mice (Geiser et al, 2013) by stimulating stem cell proliferation and differentiation of intestinal epithelium. Knockout (KO) mice lacking ZIP1, ZIP2, ZIP3 are reported to have abnormal embryogenesis under zinc-limiting conditions (Dufner-Beattie et al, 2005Peters et al, 2007).…”

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

“…Zn 2+ plays a major role in enhancing proliferation and survival of colon epithelial (colonocytes) cell cultures (Hershfinkel 2006;Cohen et al 2012a, b) as well as differentiation of colonocytes and barrier formation (Glover et al 2003(Glover et al , 2004Finamore et al 2008;Geiser et al 2012). Zinc deficiency, dietary or genetically induced by loss of the transporter that is responsible for absorption of Zn 2+ , impairs barrier function and increases permeability and cell death, and its supplementation can reverse these processes (Hoque and Binder 2006;Finamore et al 2008;Geiser et al 2013).…”