Ironjustic
Wed, Mar-12-08, 06:15
Published online before print February 2, 2008 (American
Journal of Pathology. 2008;172:738-747.) 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*
=46rom 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
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=E2. 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=E2, 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. ----------------------------
-------------------------------------------------=
----
=A9 2008 American Society for Investigative Pathology DOI:
10.2353/ajpath.2008.070097
Copyright =A9 2008 by the American Society for Investigative
Pathology.
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
Journal of Pathology. 2008;172:738-747.) 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*
=46rom 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
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=E2. 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=E2, 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. ----------------------------
-------------------------------------------------=
----
=A9 2008 American Society for Investigative Pathology DOI:
10.2353/ajpath.2008.070097
Copyright =A9 2008 by the American Society for Investigative
Pathology.
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk