Iron loading and oxidative stress in the<i>Atm</i><sup>−/−</sup>mouse liver

McDonald, Cameron; Ostini, L.; Wallace, Daniel F.; John, Abraham Neelankal; Watters, Dianne Josephine; Subramaniam, V. Nathan

doi:10.1152/ajpgi.00486.2010

Cited by 25 publications

(16 citation statements)

References 40 publications

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“…In line with findings of previous studies, in our patient there was a rapid (within 10 days after the operation) improvement of the dystonia and myoclonus at rest; dystonia and both action myoclonus and myoclonus at rest improved further during the subsequent months. In addition to A‐T, our patient was a heterozygote (H63D) for hemochromatosis that is rarely pathological in the heterozygous state, but could possibly become clinically apparent when combined with A‐T mutation, as was already shown in an animal A‐T model . Both his sister and his father, who were never diagnosed with hemochromatosis, had also had pathological LFTs.…”

Section: Case Reportsupporting

confidence: 53%

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Georgiev

Mehta

Zacharia

et al. 2016

Movement Disord Clin Pract

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Section: Case Reportsupporting

confidence: 53%

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Georgiev

Mehta

Zacharia

et al. 2016

Movement Disord Clin Pract

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“…Membranes were probed with specific antibodies: rabbit anti-FPN1 (1:1000; Alpha Diagnostic, Inc, San Antonio, TX), as previously reported, 23 and mouse anti-tubulin (1:3000; Sigma-Aldrich), followed by appropriate horseradish-peroxidase–conjugated secondary antibodies. Western blot analysis was performed by Western Lightning Ultra substrate (PerkinElmer, Waltham, MA) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Gluconeogenic Signals Regulate Iron Homeostasis via Hepcidin in Mice

Vecchi¹,

Montosi²,

Garuti³

et al. 2014

Gastroenterology

112

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Background & AimsHepatic gluconeogenesis provides fuel during starvation, and is abnormally induced in obese individuals or those with diabetes. Common metabolic disorders associated with active gluconeogenesis and insulin resistance (obesity, metabolic syndrome, diabetes, and nonalcoholic fatty liver disease) have been associated with alterations in iron homeostasis that disrupt insulin sensitivity and promote disease progression. We investigated whether gluconeogenic signals directly control Hepcidin, an important regulator of iron homeostasis, in starving mice (a model of persistently activated gluconeogenesis and insulin resistance).MethodsWe investigated hepatic regulation of Hepcidin expression in C57BL/6Crl, 129S2/SvPas, BALB/c, and Creb3l3–/– null mice. Mice were fed a standard, iron-balanced chow diet or an iron-deficient diet for 9 days before death, or for 7 days before a 24- to 48-hour starvation period; liver and spleen tissues then were collected and analyzed by quantitative reverse-transcription polymerase chain reaction and immunoblot analyses. Serum levels of iron, hemoglobin, Hepcidin, and glucose also were measured. We analyzed human hepatoma (HepG2) cells and mouse primary hepatocytes to study transcriptional control of Hamp (the gene that encodes Hepcidin) in response to gluconeogenic stimuli using small interfering RNA, luciferase promoter, and chromatin immunoprecipitation analyses.ResultsStarvation led to increased transcription of the gene that encodes phosphoenolpyruvate carboxykinase 1 (a protein involved in gluconeogenesis) in livers of mice, increased levels of Hepcidin, and degradation of Ferroportin, compared with nonstarved mice. These changes resulted in hypoferremia and iron retention in liver tissue. Livers of starved mice also had increased levels of Ppargc1a mRNA and Creb3l3 mRNA, which encode a transcriptional co-activator involved in energy metabolism and a liver-specific transcription factor, respectively. Glucagon and a cyclic adenosine monophosphate analog increased promoter activity and transcription of Hamp in cultured liver cells; levels of Hamp were reduced after administration of small interfering RNAs against Ppargc1a and Creb3l3. PPARGC1A and CREB3L3 bound the Hamp promoter to activate its transcription in response to a cyclic adenosine monophosphate analog. Creb3l3–/– mice did not up-regulate Hamp or become hypoferremic during starvation.ConclusionsWe identified a link between glucose and iron homeostasis, showing that Hepcidin is a gluconeogenic sensor in mice during starvation. This response is involved in hepatic metabolic adaptation to increased energy demands; it preserves tissue iron for vital activities during food withdrawal, but can cause excessive iron retention and hypoferremia in disorders with persistently activated gluconeogenesis and insulin resistance.

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“…Furthermore, it has been suggested that α-lipolic acid, EUK-189, CTMIO and dexamethasone can alleviate the symptoms of IR hypersensitivity, neurodegeneration and cancer susceptibility in A-T cells [15], [67]. Finally, McDonald et al [71] demonstrated that a high Fe status may determine constant oxidative stress and oxidative damage in A-T cells and therefore, antioxidant supplementation with Fe is not indicated in A-T patients.…”

Section: Future Prospects Of Antioxidant Strategies In Ataxia-telangimentioning

confidence: 99%

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

et al. 2017

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Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.

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Iron loading and oxidative stress in theAtm^−/−mouse liver

Abstract: McDonald CJ, Ostini L, Wallace DF, John AN, Watters DJ, Subramaniam VN. Iron loading and oxidative stress in the Atm Ϫ/Ϫ mouse liver.

Cited by 25 publications

References 40 publications

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Gluconeogenic Signals Regulate Iron Homeostasis via Hepcidin in Mice

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

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Iron loading and oxidative stress in theAtm−/−mouse liver

Abstract: McDonald CJ, Ostini L, Wallace DF, John AN, Watters DJ, Subramaniam VN. Iron loading and oxidative stress in the Atm Ϫ/Ϫ mouse liver.

Cited by 25 publications

References 40 publications

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia‐Telangiectasia

Gluconeogenic Signals Regulate Iron Homeostasis via Hepcidin in Mice

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

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Iron loading and oxidative stress in theAtm^−/−mouse liver