Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice

Abstract EN

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin-a transmembrane protein facilitating egress of cellular iron.

Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages.

Heme-heme oxygenase (HO) is a stress response system which reduces oxidative stress.

We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in hepatic tissues from lean and obese mice.

Obese mice exhibited hyperglycemia ( p < 0.05 ); increased levels of proinflammatory cytokines (MCP-1, IL-6, p < 0.05 ); oxidative stress ( p < 0.05 ); and increased hepatic hepcidin levels ( p < 0.05 ).

Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice ( p < 0.05 ).

However, this effect is accompanied by a significant decline in ferritin expression.

Additionally, there are reduced insulin receptor phosphorylation and attenuation of metabolic regulators pAMPK, pAKT, and pLKB1.

Cobalt protoporphyrin- (CoPP-) induced HO-1 upregulation in obese mice reversed these alterations ( p < 0.05 ), while attenuating hepatic hepcidin levels.

These effects of CoPP were prevented in obese mice concurrently exposed to an inhibitor of HO (SnMP) ( p < 0.05 ).

Our results highlight a modulatory effect of HO on iron homeostasis mediated through the suppression of hepatic hepcidin.