Hypoxia, via stabilization of HIF2 alpha, regulates the expression of the intestinal iron transporters DMT1 and ferroportin. Here we investigated whether the intestinal copper importer Ctr1 was also regulated by hypoxia. Copper uptake and Ctr1 mRNA expression were significantly increased in Caco-2 cells exposed to hypoxia. To determine whether HIF2 alpha was involved in regulation of Ctr1 expression, we employed three models of HIF2 alpha knockdown (chemical suppression of HIF2 alpha translation in Caco-2 cells; HIF2 alpha-siRNA-treated HuTu80 cells; HIF2 alpha-intestinal knockout mice); Ctr1 mRNA expression was decreased in all three models under normoxic conditions. HIF2 alpha translational inhibitor did not alter Ctr1 expression under hypoxic conditions. We conclude that basal expression of Ctr1 is regulated by HIF2 alpha; however, the induction by hypoxia is a HIF2 alpha-independent event. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.