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Nathalie Janel

Publications and source records attributed to Nathalie Janel.

14 recordsLinked to original sources
PubMed2006

Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice.

BACKGROUND/AIMS: Cystathionine beta synthase (CBS) deficiency leads to severe hyperhomocysteinemia, which confers diverse clinical manifestations, notably fatty liver. Recently, abnormal lipid metabolism has been demonstrated in CBS-deficient mice, a murine model of severe hyperhomocysteinemia. To gain further insights into effects of CBS deficiency on hepatic cholesterol metabolism, the expression of hepatic genes involved in biosynthesis, uptake and efflux was determined in CBS-deficient mice. METHODS: Gene expression analysis was performed on liver of CBS-deficient mice using quantitative real-time PCR. RESULTS: We found that CBS-deficiency in liver mice significantly increases expression of genes induced by endoplasmic reticulum stress and genes that regulate the expression of enzymes required for cholesterol and fatty acid biosynthesis and uptake, notably the scavenger receptor class B type I (SR-BI), concomitant with overexpression of SR-BI at the protein level. Moreover, we also found increased mRNA levels of ABCG5, ABCG8, ABCG1 and ABCA1, which play important roles in reverse cholesterol transport, associated with an upregulation of liver X receptors and a downregulation of the peroxisome proliferators-activated receptor alpha. CONCLUSIONS: We found that several ATP-binding cassette transporters and nuclear hormone receptors involved in liver lipid homeostasis are differentially expressed in liver of CBS-deficient mice.

Animals↗
PubMed2006

Paraoxonase-1 expression is up-regulated in Down syndrome fetal liver.

Patients with Down syndrome appear to be protected from the development of atherosclerosis. On the contrary, hyperhomocysteinemia is associated with an increased risk for atherosclerosis. As hyperhomocysteinemia due to cystathionine beta synthase deficiency is associated with a decreased expression of paraoxonase-1, a major anti-atherosclerotic component secreted by the liver, we aimed to analyze the expression of paraoxonase-1 and cystathionine beta synthase in Down syndrome fetal liver by quantitative real-time reverse transcriptase-polymerase chain reaction. Paraoxonase-1 was up-regulated in Down syndrome fetal liver, while cystathionine beta synthase gene expression in Down syndrome fetuses was similar to the gene level in control fetuses. Moreover, there was no evidence for an association between paraoxonase-1 genotypes influencing paraoxonase-1 gene expression and Down syndrome. Since most serum paraoxonase-1 is synthesized in the liver, an increase of hepatic paraoxonase-1 expression might be one of the factors which could explain the low incidence of atherosclerotic vascular disease in Down syndrome.

Aryldialkylphosphatase↗
PubMed2006

Thiol compounds metabolism in mice, rats and humans: comparative study and potential explanation of rodents protection against vascular diseases.

BACKGROUND: Rodents are often used as animal models to dissect mechanisms underlying hyperhomocysteinemia atherogenicity in humans. However, neither wild-type rodents nor cystathionine beta-synthase deficient mice develop spontaneous atherosclerosis. We investigated whether species-specific differences in thiols metabolism may explain the respective sensitivity of rodents and humans to hyperhomocysteinemia. METHODS: Thiols and vitamins B levels were determined in normohomocysteinemic humans and rodents, and in hyperhomocysteinemic mice. RESULTS: In basal status, although plasma homocysteine, cysteine and cysteinylglycine levels were lower, glutathione levels were higher in mice than in humans (4.0+/-1.6 vs. 7.9+/-2.2, P<0.0005; 147.4+/-40.3 vs. 278.5+/-50.0, P<0.0001; 2.3+/-0.7 vs. 36.6+/-7.3, P<0.0001; and 70.9+/-20.1 vs. 4.6+/-1.6, P<0.0001). Serum vitamin B12 and folate levels were 2.5- and 7.7-fold higher in rats than in humans. In wild-type mice, the increase in plasma Hcy levels induced by methionine-enriched diet was accompanied by a proportional increase in GSH levels. CONCLUSION: GSH levels are enough to modulate Hcy effects in normo- and hyperhomocysteinemic mice but not in humans. This rodents characteristic, likely supported by species differences in the relative contribution of remethylation and transsulfuration pathways, may partly explain their protection against atherosclerosis.

Animals↗
PubMed2005

Plasma homocysteine levels are not increased in murine models of Alzheimer's disease.

Alzheimer's disease (AD) patients tend to have increased plasma levels of homocysteine. However, it is unclear whether abnormality in homocysteine levels is a primary cause of Alzheimer's disease or a disease marker. In order to investigate the relative impact of Alzheimer's disease on plasma homocysteine levels, total plasma homocysteine levels were evaluated in transgenic mouse models that exhibit abnormalities in their brains that are similar to Alzheimer's patients. No significant difference was observed in blood of murine models compared to control mice, indicating that elevated plasma homocysteine level seems to be a risk marker at the most.

Alzheimer Disease↗
PubMed2005

Cystathionine beta synthase deficiency affects mouse endochondral ossification.

Cystathionine beta synthase (CBS) is a crucial regulator of plasma concentrations of homocysteine. Severe hyperhomocysteinemia due to CBS deficiency confers diverse clinical manifestations, notably characteristic skeletal abnormalities. To investigate this aspect of hyperhomocysteinemia, we analyzed the skeleton of CBS-deficient mice, a murine model of severe hyperhomocysteinemia. Radiography, Alcian Blue/Alizarin Red S-stained whole skeletal preparations, and histological comparisons were used to determine the extent, pattern, and distribution of skeletal abnormalities in CBS-deficient mice. Disruption of the murine CBS gene leads to skeletal abnormalities, notably kyphoscoliosis, with temporal shortening of long bones due to impaired cartilage differentiation, albeit to differing degrees.

Animals↗
PubMed2005

Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver.

BACKGROUND & AIMS: Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia, which confers diverse clinical manifestations, notably liver disease. To investigate this aspect of hyperhomocysteinemia, we performed a thorough investigation of liver pathology in CBS-deficient mice, a murine model of severe hyperhomocysteinemia. METHODS: The degree of liver injury and inflammation was assessed by histologic examination, by measurements of products of lipid peroxidation, and by formation of carbonyl groups on protein as a measure for the occurrence of protein oxidation. Analysis of profibrogenic, proinflammatory factors and cell apoptosis was performed by Western blots, real-time quantitative reverse-transcription polymerase chain reaction, caspase-3 activity, DNA laddering, and TUNEL assay. RESULTS: Histologic evaluation of liver specimens of 8- to 32-week-old CBS-deficient mice showed that CBS-deficient mice develop inflammation, fibrosis, and hepatic steatosis, concomitant with an enhanced expression of tissue inhibitor of metalloproteinase-1, alpha-smooth muscle actin, pro(alpha)1 collagen type I, transforming growth factor-beta1, and proinflammatory cytokines. Moreover, even if the proapoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated, caspase-3 was not activated, DNA laddering was not detected, and number of positive TUNEL cells was not increased in liver of CBS-deficient mice compared with wild-type mice. CONCLUSIONS: The results show that hyperhomocysteinemia in liver of CBS-deficient mice promotes oxidative stress, which may cause mitochondrial damage in association with activation of hepatic stellate cells, leading to liver injury. The absence of caspase-3 activation, DNA fragmentation, and TUNEL-positive cells shows that protective signals may counteract apoptotic signals in liver of CBS-deficient mice.

Animals↗
PubMed2004

Hyperkeratosis in cystathionine beta synthase-deficient mice: an animal model of hyperhomocysteinemia.

Cystathionine beta synthase (CBS) is a crucial regulator of plasma concentrations of homocysteine. Severe hyperhomocysteinemia due to CBS deficiency confers diverse clinical manifestations. Patients with severe hyperhomocysteinemia have fine hair and thin skin, but it is unclear whether these changes are related to CBS deficiency or are coincidental. To investigate these aspects of hyperhomocysteinemia, we characterized skin abnormalities of CBS-deficient mice, a murine model of severe hyperhomocysteinemia. Histological and histomorphometric analyses revealed that CBS-deficient mice have wrinkled skin with hyperkeratinosis of the epidermis and thinning of the dermis.

Animals↗
PubMed2004

The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia.

Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.

Activating Transcription Factor 2↗
PubMed2003

Altered gene expression in liver from a murine model of hyperhomocysteinemia.

Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.

Animals↗
PubMed2003

Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain.

Hyperhomocysteinemia, caused by a lack of cystathionine beta synthase (CBS), leads to elevated plasma concentrations of homocysteine. This is a common risk factor for atherosclerosis, stroke, and possibly neurodegenerative diseases. However, the mechanisms that link hyperhomocysteinemia due to CBS deficiency to these diseases are still unknown. Early biochemical studies describe developmental and adult patterns of transsulfuration and CBS expression in a variety of species. However, there is incomplete knowledge about the regional and cellular expression pattern of CBS, notably in the brain. To complete the previous data, we used in situ hybridization and Northern blotting to characterize the spatial and temporal patterns of Cbs gene expression during mouse development. In the early stages of development, the Cbs gene was expressed only in the liver and in the skeletal, cardiac, and nervous systems. The expression declined in the nervous system in the late embryonic stages, whereas it increased in the brain after birth, peaking during cerebellar development. In the adult brain, expression was strongest in the Purkinje cell layer and in the hippocampus. Immunohistochemical analyses showed that the CBS protein was localized in most areas of the brain but predominantly in the cell bodies and neuronal processes of Purkinje cells and Ammon's horn neurons.

Animals↗