Iron absorption in dysmetabolic iron overload syndrome is decreased and correlates with increased plasma hepcidin

Ruivard, M.; Lainé, Fabrice; Ganz, Tomas; Olbina, Gordana; Westerman, Mark; Nemeth, Elizabeta; Rambeau, Mathieu; Mazur, Andrzej; Gerbaud, Laurent; Tournilhac, Valérie; Abergel, Armand; Philippe, Pierre; Deugnier, Yves; Coudray, Charles

doi:10.1016/j.jhep.2009.01.029

Cited by 79 publications

(65 citation statements)

References 33 publications

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“…In NAFLD without liver iron accumulation, FPN levels were comparable to control subjects, but were significantly lower in NAFLD with hepatic iron on histology [28] . Along the same line of the observations, duodenal iron absorption was decreased in DIOS patients [124] . Obesity also represents a risk factor for an inadequate dietary iron fortification, linked to high hepcidin and low FPN expression [125] .…”

Section: What Are the Mechanisms Underlying Iron Accumulation In Nafld?supporting

confidence: 80%

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Aigner

Weiss

Datz

2014

WJH

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Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

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Section: What Are the Mechanisms Underlying Iron Accumulation In Nafld?supporting

confidence: 80%

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Aigner

Weiss

Datz

2014

WJH

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“…However, patients with DIOS had significantly less intestinal iron absorption (evaluated using stable isotopes) than subjects without hepatic siderosis or control subjects (23).…”

Section: Alterations In Duodenal Absorption Of Ironmentioning

confidence: 89%

“…Ruivard et al (23,24) hypothesized that the natural history of DIOS originates from a Western diet that is rich in fats and iron and is able to stimulate the compensatory release of hepcidin from the liver and adipose tissue. Animals fed a high-fat diet had increased activity of iron regulatory protein 1 in the liver and an increase in TfR1 expression (25).…”

Section: A High-fat Diet Changes Iron Metabolismmentioning

confidence: 99%

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

2015

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OBJECTIVEThe bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODSThe mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing b-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTSThe mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate b-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONSIron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.Iron levels help to modulate the clinical manifestations of numerous systemic diseases. The importance of adequate amounts of iron for health and well-being in humans is well known. Iron is involved in binding and transporting oxygen and regulating cell growth and differentiation, as well as electron transport, DNA synthesis, and many important metabolic processes (1).From a clinical standpoint, assessing serum ferritin concentrations is a useful measure of iron storage. Ferritin is also an acute-phase reactant and, as such, is

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“…It has been known for a long time that insulin could promote cellular iron uptake in adipocytes by stimulating recycle of the transferring receptor (TFR) between the cell membrane and the cytoplasm (Davis et al 1986, Tanner & Lienhard 1987. Results from more recent studies demonstrated (Ruivard et al 2009, Tsuchiya et al 2010 have indicated that iron absorption was decreased in DIOS patients without altering the level of serum iron, indicating that the hepatic iron overload may be associated with cellular iron uptake, which is mainly determined by the level of TFRs. It was also reported that TFR1 level was elevated obviously in patients with DIOS (Mitsuyoshi et al 2009, Tsuchiya et al 2010) and this elevation was significantly and positively correlated with the hepatic iron content (Mitsuyoshi et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway

Jiang¹,

Wang²,

Shi³

et al. 2014

Journal of Molecular Endocrinology

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Dysmetabolic iron overload syndrome (DIOS) is frequently observed, but the underlying mechanism remains unclear. We propose the hypothesis that hyperinsulinemia, a common characteristic of DIOS, may stimulate liver transferrin receptor 1 (TFR1) expression via the PI3K/iron regulatory protein 2 (IRP2) pathway, leading to the occurrence of DIOS. The hepatic iron content, serum iron parameters, and expressions of TFRs and IRPs in the liver were determined in rats with temporary or long-lasting hyperinsulinemia induced by acute or chronic administration of insulin. The effect of insulin on TFR1 expression and its molecular mechanism were determined in HL-7702 cells in vitro. It was found that longlasting hyperinsulinemia significantly increased TFR1 expression in the liver and induced mild-to-moderate hepatic iron overload, which was accompanied by a normal level of serum iron. Insulin markedly upregulated both protein and mRNA levels of TFR1 in HL-7702 cells. The stability of TFR1 mRNA stability, together with expression of IRPs expression, were both significantly increased by insulin treatment. Insulin-induced TFR1 expression was blocked by IRP2, but not by IRP1 interference, and disappeared when HL-7702 cells were pretreated with LY294002, triciribine hydrate, or rapamycin. In conclusion, the findings of this study indicate that hyperinsulnemia could induce hepatic iron overload by upregulating liver TFR1 via the PI3K/AKT/mTOR/IRP2 pathway, which may be one of the main reasons for the occurrence of DIOS.

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Iron absorption in dysmetabolic iron overload syndrome is decreased and correlates with increased plasma hepcidin

Cited by 79 publications

References 33 publications

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway

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