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

Nitin Puri,Stephen J Peterson,Athar Nawab,Robert Chao,Komal Sodhi,Krithika Srikanthan,David Sacerdoti,Vishal Hari Lakhani,Alexandra Nichols,Rebecca Klug,Yevgeniy Arefiev,Dana Sharma,Hibba Chaudry

doi:10.1155/2017/4964571

Abstract

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.

Highlights

Oxidative stress contributes to the development, and/or progression, of numerous acute and chronic pathological states
Our results show that obese mice have increased hepatic levels of hepcidin complemented by lower expression of ferroportin and ferritin with increased levels of NRF2 and gp91phox, an indication of oxidative stress
The first key finding presented in this study is the suppressive effect of heme oxygenase (HO)-1 induction on hepatic hepcidin levels in a murine model of obesity

Summary

Introduction

Oxidative stress contributes to the development, and/or progression, of numerous acute and chronic pathological states. The role of reactive oxygen species (ROS) in complex multifactorial disorders, such as obesity, fatty liver, and metabolic syndrome has received widespread attention, and obesity is characterized as a chronic lowgrade inflammatory state. In this regard, intracellular free iron is cytotoxic, drives the Fenton reaction, and exacerbates oxidative stress [1,2,3,4]. In the face of an insufficient ferritin upregulation, free iron can exert its prooxidant and cytotoxic effects These molecular events feed-forward on ROS and contribute to the escalation of pathophysiological alterations in conditions, such as NAFLD and obesity [1,2,3, 8, 9]. The crucial importance of ferritin in the protection of the liver to oxidative insult is further corroborated in ischemia reperfusion injury [10]

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Conclusion