Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice
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 en...
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| Format: | Article |
| Language: | English |
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Wiley
2017-01-01
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| Series: | Journal of Nutrition and Metabolism |
| Online Access: | http://dx.doi.org/10.1155/2017/4964571 |
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| author | Nitin Puri Yevgeniy Arefiev Robert Chao David Sacerdoti Hibba Chaudry Alexandra Nichols Krithika Srikanthan Athar Nawab Dana Sharma Vishal Hari Lakhani Rebecca Klug Komal Sodhi Stephen J. Peterson |
| author_facet | Nitin Puri Yevgeniy Arefiev Robert Chao David Sacerdoti Hibba Chaudry Alexandra Nichols Krithika Srikanthan Athar Nawab Dana Sharma Vishal Hari Lakhani Rebecca Klug Komal Sodhi Stephen J. Peterson |
| author_sort | Nitin Puri |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-27995bdb4a5d4e149d2501b7731c3999 |
| institution | Kabale University |
| issn | 2090-0724 2090-0732 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nutrition and Metabolism |
| spelling | doaj-art-27995bdb4a5d4e149d2501b7731c39992025-02-03T05:54:01ZengWileyJournal of Nutrition and Metabolism2090-07242090-07322017-01-01201710.1155/2017/49645714964571Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese MiceNitin Puri0Yevgeniy Arefiev1Robert Chao2David Sacerdoti3Hibba Chaudry4Alexandra Nichols5Krithika Srikanthan6Athar Nawab7Dana Sharma8Vishal Hari Lakhani9Rebecca Klug10Komal Sodhi11Stephen J. Peterson12Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USADepartment of Medicine, Weill Cornell Medicine/NYP Brooklyn Methodist Hospital, Brooklyn, NY 11215, USADepartment of Medicine, Weill Cornell Medicine/NYP Brooklyn Methodist Hospital, Brooklyn, NY 11215, USADepartment of Clinical and Experimental Medicine, University of Padova, Padoua, ItalyDepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartments of Medicine and Physiology, Marshall University School of Medicine, Huntington, WV, USADepartment of Medicine, Weill Cornell Medicine/NYP Brooklyn Methodist Hospital, Brooklyn, NY 11215, USAHepcidin, 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.http://dx.doi.org/10.1155/2017/4964571 |
| spellingShingle | Nitin Puri Yevgeniy Arefiev Robert Chao David Sacerdoti Hibba Chaudry Alexandra Nichols Krithika Srikanthan Athar Nawab Dana Sharma Vishal Hari Lakhani Rebecca Klug Komal Sodhi Stephen J. Peterson Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice Journal of Nutrition and Metabolism |
| title | Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice |
| title_full | Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice |
| title_fullStr | Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice |
| title_full_unstemmed | Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice |
| title_short | Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice |
| title_sort | heme oxygenase induction suppresses hepatic hepcidin and rescues ferroportin and ferritin expression in obese mice |
| url | http://dx.doi.org/10.1155/2017/4964571 |
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