Published online before print February 2, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070097

Accepted for publication November 26, 2007.

Article

Iron Depletion by Deferoxamine Up-Regulates Glucose Uptake and Insulin Signaling in Hepatoma Cells and in Rat Liver

Paola Dongiovanni^*, Luca Valenti^*, Anna Ludovica Fracanzani^*, Stefano Gatti, Gaetano Cairo, and Silvia Fargion^*@

From the Departments of Internal Medicine,* and Transplantation and Experimental Surgery, Ospedale Maggiore Policlinico Mangiagalli Regina Elena Istituto Ricovero e Cura a Carattere Scientifico, and the Department of General Pathology, University of Milano, Milano, Italy

^@ To whom correspondence should be addressed. E-mail: silvia.fargion{at}unimi.it.

	Abstract

Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized HIF-1 and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl₂ and required the HIF-1 obligate partner ARNT/HIF-1. Iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. Iron depletion of Sprague-Dawley rats increased HIF-1 expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. In rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes in vitro and in vivo.