Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C

Sato, Masanori; Miyanishi, Koji; Tanaka, Shingo; Sakurada, Akira; Sakamoto, Hiroki; Kawano, Yutaka; Takada, Kohichi; Kobune, Masayoshi; Kato, Junji

doi:10.1155/2018/2154361

Cited by 6 publications

(5 citation statements)

References 42 publications

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“…Our results showed that hepcidin significantly downregulated several iron transporters and iron transport-associated proteins at mRNA and protein level, especially TfR1, DMT1 and FPN ( Fig 3 ). Corresponding to these results, previous studies also showed that hepcidin suppressed DMT1 and FPN expression in Caco-2, brain microvascular endothelial cells (BMECs) and BKO mice [ 15 , 18 , 22 , 49 , 50 , 56 ]. It has been shown that hepcidin could directly interact with FPN on the basolateral side of enterocytes to activate FPN internalization and degradation [ 57 – 59 ].…”

Section: Discussionsupporting

confidence: 67%

Hepcidin induces intestinal calcium uptake while suppressing iron uptake in Caco-2 cells

et al. 2021

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Abnormal calcium absorption and iron overload from iron hyperabsorption can contribute to osteoporosis as found in several diseases, including hemochromatosis and thalassemia. Previous studies in thalassemic mice showed the positive effects of the iron uptake suppressor, hepcidin, on calcium transport. However, whether this effect could be replicated in other conditions is not known. Therefore, this study aimed to investigate the effects of hepcidin on iron and calcium uptake ability under physiological, iron uptake stimulation and calcium uptake suppression. To investigate the potential mechanism, effects of hepcidin on the expression of iron and calcium transporter and transport-associated protein in Caco-2 cells were also determined. Our results showed that intestinal cell iron uptake was significantly increased by ascorbic acid together with ferric ammonium citrate (FAC), but this phenomenon was suppressed by hepcidin. Interestingly, hepcidin significantly increased calcium uptake under physiological condition but not under iron uptake stimulation. While hepcidin significantly suppressed the expression of iron transporter, it had no effect on calcium transporter expression. This indicated that hepcidin-induced intestinal cell calcium uptake did not occur through the stimulation of calcium transporter expression. On the other hand, 1,25(OH)2D3 effectively induced intestinal cell calcium uptake, but it did not affect intestinal cell iron uptake or iron transporter expression. The 1,25(OH)2D3-induced intestinal cell calcium uptake was abolished by 12 mM CaCl2; however, hepcidin could not rescue intestinal cell calcium uptake suppression by CaCl2. Taken together, our results showed that hepcidin could effectively and concurrently induce intestinal cell calcium uptake while reducing intestinal cell iron uptake under physiological and iron uptake stimulation conditions, suggesting its therapeutic potential for inactive calcium absorption, particularly in thalassemic patients or patients who did not adequately respond to 1,25(OH)2D3.

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Section: Discussionsupporting

confidence: 67%

Hepcidin induces intestinal calcium uptake while suppressing iron uptake in Caco-2 cells

et al. 2021

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“…Hepcidin production and its antiviral action may be reduced by HCV. Low serum hepcidin levels may in turn increase duodenal absorption of iron by up‐regulating duodenal ferroportin, and the increased intracellular iron content may suppress HCV replication in a negative feedback loop . The net effect of these counterbalancing actions may depend on the relative strength of the inherent response to raise hepcidin levels in response to iron overload and the prowess of HCV to circumvent the antiviral action of hepcidin by suppressing transcriptional activity of the HAMP gene …”

Section: Resultsmentioning

confidence: 99%

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Czaja

2019

Aliment Pharmacol Ther

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Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. Aims:To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management Methods: English abstracts were identified in PubMed by multiple search terms.Full length articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. Conclusions:Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.

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“…The blots, blocked with 3% BSA for 1 h at room temperature, were incubated with primary antibody (FPN1, 1:1,000, AIT-001; Alomone Laboratories, Jerusalem, Israel; or DMT1, 1:4,000, ab55735; Abcam, Cambridge, United Kingdom; or ␤-actin, 1:1,000, no. 4970; Cell Signaling Technology, Danvers, MA; 12,26,42,50). Following an overnight incubation at 4°C, the blots, washed with Tris-buffered saline-Tween 20 (5 min ϫ 5), were placed in goat anti-rabbit horseradish peroxidase-conjugated secondary antibody (1:20,000) for 2 h at room temperature.…”

Section: Subject Recruitmentmentioning

confidence: 99%

Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon

Minor

Kupec

Nickerson

et al. 2020

American Journal of Physiology-Cell Physiology

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Iron deficiency anemia is a common complication of ulcerative colitis (UC) that can profoundly impact quality of life. Most iron absorption occurs in the duodenum via divalent metal transporter 1 (DMT1)-mediated uptake and ferroportin-1 (FPN1)-mediated export across the apical and basolateral membranes, respectively. However, the colon also contains iron transporters and can participate in iron absorption. Studies have shown increased duodenal DMT1 and FPN1 in patients with UC, but there is conflicting evidence about whether expression is altered in UC colon. We hypothesized that expression of colonic DMT1 and FPN1 will also increase to compensate for iron deficiency. Quantitative RT-PCR and Western blot analyses were performed on duodenal and colonic segmental (right colon, transverse colon, left colon, and rectum) biopsies obtained during colonoscopy. DMT1 mRNA and protein abundances in colonic segments were approximately equal to those in the duodenum, whereas colonic FPN1 mRNA and protein abundances of colonic segments were about one-quarter of those of the duodenum. DMT1 specific mRNA and protein abundances were increased twofold, whereas FPN1 mRNA and protein expressions were increased fivefold in UC distal colon. Immunofluorescence studies revealed enhanced expression of apical membrane- and basolateral membrane-localized DMT1 and FPN1 in UC human colon, respectively. Increased DMT1 expression was associated with enhanced 2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea (CISMBI, DMT1 specific inhibitor)-sensitive 59Fe uptake in UC human colon. We conclude from these results that patients with active UC have increased expression of colonic iron transporters and increased iron absorption, which may be targeted in the treatment of UC-related anemia.

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Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C

Cited by 6 publications

References 42 publications

Hepcidin induces intestinal calcium uptake while suppressing iron uptake in Caco-2 cells

Hepcidin induces intestinal calcium uptake while suppressing iron uptake in Caco-2 cells

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon

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