Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi, Federico; Ahmad, Ghayyor; Ramadori, Pierluigi; Malik, Ihtzaz Ahmed; Sheikh, Nadeem; Merli, Manuela; Riggio, Oliviero; Dudás, József; Ramadori, Giuliano

doi:10.1038/labinvest.2009.92

Cited by 18 publications

(16 citation statements)

References 47 publications

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“…As shown in Table 2, there were no significant changes in both ALT and T-BIL among groups injected with various doses of GdCl 3 , suggesting that GdCl 3 does not affect liver function. These results are consistent with previously reported finding [28,29]. When zymosan was used to stimulate the Kupffer cells, the AUC, ΔR 2 max , and ΔR 2 last values increased significantly with increasing dose (Fig.…”

Section: Discussionsupporting

confidence: 93%

Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model

Murase

Assanai

Takata

et al. 2015

Magnetic Resonance Imaging

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Section: Discussionsupporting

confidence: 93%

Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model

Murase

Assanai

Takata

et al. 2015

Magnetic Resonance Imaging

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“…Downregulation of Hjv and Heph expression in this study confirms previous studies [12,15,28] in different rat models of extrahepatic and intrahepatic APR that Hepc and Hjv-Heph gene expression together with Fpn-1 changes simultaneously and in an opposite direction. The same results occurred in rats after oral administration of tacrolimus; an early upregulation of Hepc gene expression associated with time-dependent downregulation of Fpn-1, Hjv, and Heph gene expression was observed.…”

Section: Discussionsupporting

confidence: 91%

Immunosuppressant-Induced Oxidative Stress and Iron: A Paradigm Shift from Systemic to Intrahepatic Abnormalities

Akhtar

Ali

Sheikh

2020

Oxidative Medicine and Cellular Longevity

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Immunosuppressants are used clinically to lower rejection rates in transplant patients. Unfortunately, the adverse side effects of these immunosuppressants can be severe, which is one of the rationales that life expectancy of individuals after transplant still significantly falls short of that of the general population. The current experimental setup was designed to analyze the tacrolimus-induced hepatic iron overload in Wistar rats. Four experimental groups were orally given 1 ml of aqueous suspension of tacrolimus (12 mg/kg) through oral gavage, and rats were sacrificed after 6, 12, 24, and 48 h of tacrolimus dose. Hepatic hepcidin expression was found to be significantly augmented along with the upregulation of Tf and TfR1, Ferritin-L, Ferritin-H, TNF-α, and HO-1 gene expression at 6 and 12 h, and downregulation of Fpn-1, Hjv, and Heph at 6 h was detected. Significant downregulation of IL-6, IFN-α, IFN-β, and IFN-γ at all study time points was also observed. Serum iron level was decreased while serum hepcidin level was found to be significantly increased. Iron staining showed blue-stained hemosiderin granules within the hepatocytes, sinusoidal spaces, and portal areas at 12 and 24 h time points and remarkable fall of iron contents in the splenic red pulp. These results suggest that the use of tacrolimus leads to the onset of an intrahepatic acute-phase response-like reaction and causes iron overload in hepatic cells by altering the expression of key proteins involved in iron metabolism.

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“…47,48 In fact, the findings presented here are consistent with earlier studies obtained at RNA level, wherein a downregulation of Fpn-1-specific transcripts occurred in parallel with an increase in the level of the acute-phase cytokines (IL-6, IL-1b and TNF-a) reported in different rat models. [48][49][50] Furthermore, in our current study, treatment of rat hepatocytes with cytokines (IL-6, IL-1b and TNF-a) reduced the Fpn-1 gene expression; however, the impact of IL-6 was the strongest compared with that induced by the two other cytokines. Taken together, it became evident that early-observed hepatic Fpn-1 reduction could be due to direct effect of the acute-phase cytokines, 25,48 whereas late decrease in Fpn-1 protein could be due to the combination of both hepcidin and the acute-phase cytokines.…”

Section: Discussionmentioning

confidence: 39%

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

Naz

Malik

Sheikh

et al. 2012

Laboratory Investigation

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Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1b and TNF-a) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of a2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver behaves as a 'sponge' for iron under acute-phase conditions, and Fpn-1 behaves as a negative acute-phase protein in rat hepatocytes mainly, but not exclusively, because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR. The liver is the central organ for iron metabolism. 1 Liver cells (hepatocytes) take up iron absorbed from the diet, and Kupffer cells take up iron from aged erythrocytes and distribute it to different organs. Iron is an important co-factor for oxygen transport, heme and non-heme iron proteins, electron transfer, neurotransmitter synthesis, myelin production, energy metabolism and mitochondrial function, as well as for the production of reactive-oxygen species. 2,3 As a result, its metabolism is tightly regulated. Iron homeostasis is controlled by a large group of iron-regulatory proteins. The absorption of dietary iron begins with its transport across the duodenal brush-border membrane mediated by the duodenal metal transporter-1 (DMT-1), the major iron transporte...

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Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Cited by 18 publications

References 47 publications

Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model

Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model

Immunosuppressant-Induced Oxidative Stress and Iron: A Paradigm Shift from Systemic to Intrahepatic Abnormalities

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

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