Crucial Role of FLVCR1a in the Maintenance of Intestinal Heme Homeostasis

Fiorito, Veronica; Forni, Marco; Silengo, Lorenzo; Altruda, Fiorella; Tolosano, Emanuela

doi:10.1089/ars.2014.6216

Cited by 34 publications

(52 citation statements)

References 36 publications

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“…However, these mechanisms fail to completely protect the cells from heme toxicity, especially under stress conditions, resulting in oxidative stress and increased susceptibility to programmed cell death. These data are in agreement with previous studies indicating an essential role for FLVCR1a to prevent heme-induced oxidative stress in different cell types[21, 22]. …”

Section: Discussionsupporting

confidence: 94%

“…We previously reported that FLVCR1a is essential to prevent heme-induced oxidative stress in several cell types, including erythroid progenitors, hepatocytes and intestinal cells[21, 22, 33]. To get an insight into the role of FLVCR1a in neuronal cells, shRNA-mediated knockdown experiments were performed in SH-SY5Y neuroblastoma cells (Fig 4A and S2 Fig).…”

Section: Resultsmentioning

confidence: 99%

“…However, excess free-heme is highly toxic due to its ability to promote oxidative stress, proteasome inhibition and mitochondrial dysfunction, that ultimately lead to cell death[26–28]. For this reason, the intracellular free-heme pool is finely regulated at multiple levels[26] and FLVCR1a-mediated heme export contributes to this process[21, 22, 26]. Our data show that primary fibroblasts and lymphoblastoid cell lines from patients with sensory neurodegeneration have reduced heme export activity due to FLVCR1-mutations.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

et al. 2016

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Pain is necessary to alert us to actual or potential tissue damage. Specialized nerve cells in the body periphery, so called nociceptors, are fundamental to mediate pain perception and humans without pain perception are at permanent risk for injuries, burns and mutilations. Pain insensitivity can be caused by sensory neurodegeneration which is a hallmark of hereditary sensory and autonomic neuropathies (HSANs). Although mutations in several genes were previously associated with sensory neurodegeneration, the etiology of many cases remains unknown. Using next generation sequencing in patients with congenital loss of pain perception, we here identify bi-allelic mutations in the FLVCR1 (Feline Leukemia Virus subgroup C Receptor 1) gene, which encodes a broadly expressed heme exporter. Different FLVCR1 isoforms control the size of the cytosolic heme pool required to sustain metabolic activity of different cell types. Mutations in FLVCR1 have previously been linked to vision impairment and posterior column ataxia in humans, but not to HSAN. Using fibroblasts and lymphoblastoid cell lines from patients with sensory neurodegeneration, we here show that the FLVCR1-mutations reduce heme export activity, enhance oxidative stress and increase sensitivity to programmed cell death. Our data link heme metabolism to sensory neuron maintenance and suggest that intracellular heme overload causes early-onset degeneration of pain-sensing neurons in humans.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

et al. 2016

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“…Accumulation of ROS in heart homogenates or cells was assessed by using the oxidant-sensitive fluorescent dye 29,79-dichlorodihydrofluoroscein diacetate (H2DCFDA; Molecular Probes, Inc., Eugene, OR) as previously described [32]. Heart homogenates or cell extracts were incubated with 5uM H2DCFDA in phosphate buffered saline (PBS) or in serum-free medium, respectively, for 30 min at 37 °C under 5% CO2 atmosphere.…”

Section: Ros Production Assaymentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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Heart failure is a leading cause of morbidity and mortality in patients affected by different disorders associated to intravascular hemolysis. The leading factor is the presence of pathologic amount of pro-oxidant free heme in the bloodstream, due to the exhaustion of the natural heme scavenger Hemopexin (Hx). Here, we evaluated whether free heme directly affects cardiac function, and tested the therapeutic potential of replenishing serum Hx for increasing serum heme buffering capacity.The effect of heme on cardiac function was assessed in vitro, on primary cardiomyocytes and H9c2 myoblast cell line, and in vivo, in Hx -/-mice and in genetic and acquired mouse models of intravascular hemolysis. Purified Hx or anti-oxidants N-Acetyl-L-cysteine and α-tocopherol were used to counteract heme cardiotoxicity.In mice, Hx loss/depletion resulted in heme accumulation and enhanced reactive oxygen species (ROS) production in the heart, which ultimately led to severe systolic dysfunction. Similarly, high ROS reduced systolic Ca 2+ transient amplitudes and fractional shortening in primary cardiomyocytes exposed to free heme. In keeping with these Ca 2+ handling alterations, oxidation and CaMKIIdependent phosphorylation of Ryanodine Receptor 2 were higher in Hx -/-hearts than in controls.Administration of anti-oxidants prevented systolic failure both in vitro and in vivo. Intriguingly, Hx rescued contraction defects of heme-treated cardiomyocytes and preserved cardiac function in hemolytic mice.We show that heme-mediated oxidative stress perturbs cardiac Ca 2+ homeostasis and promotes contractile dysfunction. Scavenging heme, Hx counteracts cardiac heme toxicity and preserves left ventricular function. Our data generate the rationale to consider the therapeutic use of Hx to limit the cardiotoxicity of free heme in hemolytic disorders.

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“…The depletion of FLVCR1 led to excess heme content in erythroid progenitors, and in consequence, increased cytoplasmic ROS and apoptosis, whereas restoring FLVCR1 gene expression returned to normal erythropoiesis, demonstrating that excess of intracellular heme levels disrupted this cellular process 12–14 . Recent studies demonstrated the importance of FLVCR1 in the maintenance of heme homeostasis in other tissues, including intestine 15 and liver 16 . Interestingly, the disruption of FLVCR1 in these tissues resulted in increased tissue heme accumulation in parallel to increased heme oxygenase 1 (HMOX1) and markers of oxidative stress and iron accumulations (ferroportin and ferritin levels) 15, 16 .…”

Section: Introductionmentioning

confidence: 99%

Increased adipose tissue heme levels and exportation are associated with altered systemic glucose metabolism

Moreno-Navarrete

Rodríguez

Ortega

et al. 2017

Sci Rep

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Iron status is known to be associated with the physiology of adipose tissue (AT). We aimed to investigate AT heme and expression of heme exporter (FLVCR1) in association with obesity and type 2 diabetes (T2D). Substantial amounts of FLVCR1 mRNA and protein levels were detected in AT, being significantly increased in subjects with T2D, and positively correlated with fasting glucose, fasting triglycerides and with circulating markers of iron stores (serum ferritin, blood hemoglobin and hematocrit). In both visceral (VAT) and subcutaneous AT (SAT), increased heme levels were found in subjects with T2D. Reinforcing these associations, FLVCR1 mRNA levels were positively linked to fasting glucose in an independent cohort. Longitudianlly, the percent change of FLVCR1 positively correlated with the percent change in fasting glucose (r = 0.52, p = 0.03) after bariatric surgery-induced weight loss. High-fat diet-induced weight gain in rats did not result in significant changes in AT Flvcr1 mRNA but, remarkably, the expression of this gene positively correlated with fasting glucose and negatively with insulin sensitivity (QUICKI). Altogether, these findings showed a direct association between FLVCR1 mRNA levels and hyperglycemia, suggesting that increased adipose tissue heme exportation might disrupt, or is the consequence of, impaired systemic glucose metabolism during the progression to T2D.

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Crucial Role of FLVCR1a in the Maintenance of Intestinal Heme Homeostasis

Cited by 34 publications

References 36 publications

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Increased adipose tissue heme levels and exportation are associated with altered systemic glucose metabolism

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