Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress

Clothier, Bruce; Robinson, Susan W.; Akhtar, Ruth; Francis, Jean E.; Raja, Kishor B.; Smith, Andrew G.

doi:10.1016/s0006-2952(99)00306-8

Cited by 37 publications

(46 citation statements)

References 39 publications

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“…If so, understanding the nature of this modifier might provide insights into the human pathophysiology of disease. We are currently testing this hypothesis by back-crossing Pank2 in a variety of backgrounds, including AKR and SWR strains, which have high endogenous levels of iron (Clothier et al 2000;Fleming et al 2001), as strain backgrounds can influence manifestation of disease (Buchner et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Kuo

Hayflick

Gitschier

2007

J of Inher Metab Disea

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SummaryWe asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B 5 ), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden-Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PAdeficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16-17 s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Kuo

Hayflick

Gitschier

2007

J of Inher Metab Disea

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“…Non-heme iron in liver and spleen was quantitated by the method of Torrance and Bothwell as previously reported 22,23 Levels are expressed as micrograms of Fe per gram of wet tissue. The non-heme iron level in the diet was 143 g Fe/g.…”

Section: Methodsmentioning

confidence: 99%

“…[22][23][24]36 Figure 1 illustrates the distribution of non-heme iron by Perls' stain in the liver and spleen of fully adult mice. Whereas there was little staining of hepatocytes and only positive-staining of occasional Kupffer cells in C57BL/6J mouse liver, there was pronounced staining in SWR mouse liver, mainly of hepatocytes but also of some Kupffer cells (Fig.…”

Section: Distribution Of Iron In Parental Strainsmentioning

confidence: 99%

“…To investigate the genetic basis of the strain variation in levels of liver and spleen iron, an F 2 intercross between the parent C57BL/6J and SWR strains was examined at 6-8 weeks (Table 2), when divergence in iron status was still developing. 23 In addition to a marked difference between the parental strains, there was a propensity for female C57BL/6J F 1 and F 2 mice to have greater iron contents than males. This was not detected at this age in the SWR parental animals.…”

Section: Distribution Of Iron In Parental Strainsmentioning

confidence: 99%

“…[20][21][22][23][24][25][26][27] C57BL strains show much lower iron than some others, with SWR mice having much higher levels of hepatic and splenic iron, which may explain their different responses to toxins, infection, and age-related changes. [22][23][24]28 In this article, we show the location and contribution of polymorphic genes that determine basal iron status in apparently normal individuals using quantitative trait loci (QTL) analysis of an intercross between C57BL/6J and SWR mice.…”

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confidence: 99%

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Multiple polymorphic loci determine basal hepatic and splenic iron status in mice

Grant¹,

Robinson²,

Edwards³

et al. 2006

Hepatology

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Polymorphisms of genes linked to iron metabolism may account for individual variability in hemochromatosis and iron status connected with liver and cardiovascular diseases, cancers, toxicity, and infection. Mouse strains exhibit marked differences in levels of non-heme iron, with C57BL/6J and SWR showing low and high levels, respectively. The genetic basis for this variability was examined using quantitative trait loci (QTL) analysis together with expression profiling and chromosomal positions of known iron-related genes. Non-heme iron levels in liver and spleen of C57BL/6J ؋ SWR F 2 mice were poorly correlated, indicating independent regulation. Highly significant (P < .01) polymorphic loci were found on chromosomes 2 and 16 for liver and on chromosomes 8 and 9 for spleen. With sex as a covariate, additional significant or suggestive (P < 0.1) QTL were detected on chromosomes 7, 8, 11, and 19 for liver and on chromosome 2 for spleen. A gene array showed no clear association between most loci and differential iron-related gene expression. The gene for transferrin and a transferrin-like gene map close to the QTL on chromosome 9. Transferrin saturation was significantly lower in C57BL/6J mice than in SWR mice, but there was no significant difference in the serum level of transferrin, hepatic expression, or functional change in cDNA sequence. ␤2-Microglobulin, which, unlike other loci, was associated with C57BL/6J alleles, is a candidate for the chromosome 2 QTL for higher iron. In conclusion, the findings show the location of polymorphic genes that determine basal iron status in wild-type mice. Human equivalents may be pertinent in predisposition to hepatic and other disorders. (HEPATOLOGY 2006;44:174-185.)

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Strain‐ and time‐dependent alterations in hepatic iron metabolism in a murine model of nonalcoholic steatohepatitis

Bloomer

Olivier

Bergmann

et al. 2016

Cell Biochemistry & Function

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Nonalcoholic steatohepatitis (NASH) is a common liver disease that often accompanies the metabolic syndrome. The latter condition has been linked to iron deficiency and diminished intestinal iron absorption, likely the result of hepcidin upregulation by chronic inflammation. Paradoxically, some NASH patients accumulate excess hepatic iron, which may increase fibrosis and cancer risk. Iron accumulation has been attributed to suppression of hepcidin by oxidative stress. The objective of this study was to investigate the contributions of inflammation and oxidative stress to altered hepatic iron metabolism in a murine model of NASH using inbred strains of mice with differing susceptibilities to injury.

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Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress

Cited by 37 publications

References 39 publications

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Multiple polymorphic loci determine basal hepatic and splenic iron status in mice

Strain‐ and time‐dependent alterations in hepatic iron metabolism in a murine model of nonalcoholic steatohepatitis

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