scholarly journals Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Blood ◽  
2020 ◽  
Vol 136 (6) ◽  
pp. 726-739 ◽  
Author(s):  
Yingying Yu ◽  
Li Jiang ◽  
Hao Wang ◽  
Zhe Shen ◽  
Qi Cheng ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Metal Binding ◽  
Iron Homeostasis ◽  
Protective Role ◽  
Hepatic Iron ◽  
Serum Transferrin ◽  
Dietary Iron ◽  
High Iron ◽  
Healthy Control ◽  
Metal Binding Protein

Abstract Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

TCDD promotes liver fibrosis through disordering systemic and hepatic iron homeostasis

2020 ◽  
Vol 395 ◽  
pp. 122588 ◽  
Author(s):  
Changying Li ◽  
Yingying Liu ◽  
Zheng Dong ◽  
Ming Xu ◽  
Ming Gao ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Homeostasis ◽  
Hepatic Iron

Ceruloplasmin Is Essential for the Mobilization of Tissue Iron Stores.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3581-3581
Author(s):  
Seth Rivera ◽  
Miguel Lopez ◽  
Dina Farshidi ◽  
Victoria Gabayan ◽  
Tomas Ganz
Keyword(s):  
Iron Deficiency ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
Extracellular Fluid ◽  
Deficiency Anemia ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Stores ◽  
High Iron ◽  
Iron Deficient

Abstract In extracellular fluid, iron is in the ferric (oxidized form) but the intracellular form is ferrous iron (reduced). The outflow of iron from cells is dependent on oxidase activity that converts ferrous to ferric iron. Iron-absorbing enterocytes possess a unique iron oxidase, hephaestin. It is presumed that the circulating hephaestin paralog ceruloplasmin fulfils this role in hepatocytes and macrophages. The DiSnA mouse lacks ceruloplasmin. We hypothesized that iron homeostasis in this mouse would be unusually dependent on dietary iron because the mouse would not be able to mobilize iron from tissue stores in hepatocytes and macrophages. We fed 4-week-old DiSnA and wildtype (WT) mice a high iron (1%) diet for 4 weeks to load tissue stores. We then switched them to an iron-deficient diet and analyzed them weekly to measure iron and hemoglobin concentrations. Even on the high iron diet, DiSnA mice had lower serum iron concentrations than WT control (32.9±17.9 vs. 53.5±17.6 μM, p=0.05) but after two weeks on the iron deficient diet, the DiSnA mice had almost undetectable serum iron (4.2±1.8 μM) whereas the WT controls had only declined slightly (43.2±9.6 μM, p<0.001). Iron saturation followed a similar trend. Neither WT nor DiSnA mice were anemic at baseline (Hgb = 13.9±0.3 and 13.9±1.1 g/dL, respectively; p=0.994) but by the end of two weeks, the DiSnA mice had developed anemia whereas the WT mice had not (Hgb = 10.4±0.5 vs. 12.6±0.5 g/dL; p<0.001). The difference in hemoglobin concentrations persisted to the 6-week timepoint (Hgb = 8.4±0.5 vs. 12.6±1.4; p<0.001). After 6-weeks on a low iron diet, iron was still present in livers and spleens of both groups. Ceruloplasmin is essential for the mobilization of iron stores to protect against iron deficiency anemia in response to periods of dietary iron deficiency.

Comparison of localization of metallothionein in tissues of metallothionein-deficient mice

1995 ◽  
Vol 53 ◽  
pp. 1042-1043
Author(s):  
H. Nishimura ◽  
R Nishimura ◽  
D.L. Adelson ◽  
A.E. Michaelska ◽  
K.H.A. Choo ◽  
...  
Keyword(s):  
Metal Binding ◽  
Immunohistochemical Staining ◽  
Squamous Epithelium ◽  
Rabbit Antiserum ◽  
Slight Modification ◽  
Positive Control ◽  
Heavy Metal Binding ◽  
Critical Organ ◽  
Metal Binding Protein ◽  
Deficient Mice

Metallothionein (MT), a cysteine-rich heavy metal binding protein, has several isoforms designated from I to IV. Its major isoforms, I and II, can be induced by heavy metals like cadmium (Cd) and, are present in various organs of man and animals. Rodent testes are a critical organ to Cd and it is still a controversial matter whether MT exists in the testis although it is clear that MT is not induced by Cd in this tissue. MT-IV mRNA was found to localize within tongue squamous epithelium. Whether MT-III is present mainly glial cells or neurons has become a debatable topic. In the present study, we have utilized MT-I and II gene targeted mice and compared MT localization in various tissues from both MT-deficient mice and C57Black/6J mice (C57BL) which were used as an MT-positive control. For MT immunostaining, we have used rabbit antiserum against rat MT-I known to cross-react with mammalian MT-I and II and human MT-III. Immunohistochemical staining was conducted by the method described in the previous paper with a slight modification after the tissues were fixed in HistoChoice and embedded in paraffin.

scholarly journals The liver in regulation of iron homeostasis

2017 ◽  
Vol 313 (3) ◽  
pp. G157-G165 ◽  
Author(s):  
Gautam Rishi ◽  
V. Nathan Subramaniam
Keyword(s):  
Plasma Proteins ◽  
Iron Homeostasis ◽  
Vital Role ◽  
Regulatory Function ◽  
Hepatic Iron ◽  
Storage Site ◽  
Molecular Processes ◽  
Body Iron ◽  
Functionally Diverse ◽  
And Storage

The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body’s metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism.

scholarly journals Galectin-3 as a Novel Multifaceted and Not Only Cardiovascular Biomarker in Patients with Psoriasis with Regard to Systemic Treatment—Preliminary Data

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 88
Author(s):  
Anna Baran ◽  
Paulina Kiluk ◽  
Julia Nowowiejska ◽  
Tomasz W. Kaminski ◽  
Magdalena Maciaszek ◽  
...  
Keyword(s):  
Protective Role ◽  
Control Group ◽  
Plaque Type ◽  
Before And After ◽  
Diagnostic Role ◽  
Galectin 3 ◽  
Healthy Control ◽  
History Of ◽  
Cardiovascular Biomarker ◽  
Positive Correlations

Galectin-3 (gal-3) is a multifunctional regulator of various biological processes and diseases, which are common comorbidities in psoriasis. Data regarding potential diagnostic role of gal-3 in psoriasis are insufficient. Serum gal-3 levels were evaluated before and after twelve weeks of treatment with acitretin or methotrexate in 31 patients with plaque-type psoriasis and compared to 11 healthy control group. The mean serum galectin-3 level in patients with psoriasis was significantly higher compared to the control group (p < 0.01). In patients with obesity and long-lasting psoriasis (>20 years) positive relations of gal-3 and PASI were noted. In psoriatics with low gal-3 levels, positive correlations between the gal-3 and BMI, glucose level, and with the latter in short-lasting psoriasis (<20 years) were noted. In the long history of psoriasis, gal-3 was negatively correlated with lipids levels. The Gal-3 level might be a multifaceted modulator of the course of psoriasis and predictive factor of cardiometabolic comorbidities’ development, especially in patients with a long history of the disease or obesity. Patients with low serum gal-3 and short history of psoriasis are presumably at greater risk of diabetes. In patients with long-lasting psoriasis and concomitant obesity, gal-3 may exert a protective role against dyslipidemia or perhaps further CMD development.

Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Emanuele Angelucci ◽  
Pietro Muretto ◽  
Antonio Nicolucci ◽  
Donatella Baronciani ◽  
Buket Erer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Content ◽  
Hazard Rate ◽  
Iron Concentration ◽  
Dry Weight ◽  
Interquartile Range ◽  
Hepatic Iron ◽  
Fibrosis Progression

Abstract To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 ± 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

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