Génétique du rat hypertendu de souche lyonnaise (étude des chromosomes 13 et 17 à l aide d une approche consomique)

L hypertension artérielle essentielle est une maladie polyfactorielle résultant de l interaction entre de multiples facteurs génétiques et environnementaux qui restent, pour la plupart, à déterminer. Le rat génétiquement hypertendu de souche lyonnaise (LH) est un modèle d hypertension essentielle qui présente également des signes évoquant un syndrome métabolique (surcroît pondéral, hyperlipidémie spontanée et augmentation du rapport insuline/glucose plasmatique). Une analyse de coségrégation effectuée chez des hybrides de seconde génération issus du croisement entre rats LH et rats normotendus LN a mis en évidence des loci quantitatifs d intérêt (QTLs) influençant la pression artérielle sur les chromosomes 13 et 17. Afin de déterminer l importance fonctionnelle des chromosomes 13 et 17, nous avons substitué, chez des rats LH, chacun de ces chromosomes par le chromosome correspondant provenant de rats normotendus Brown Norway (BN). Ces souches, dites consomiques, ainsi que les souches parentales LH et BN ont été phénotypées. Ce travail a montré l influence du chromosome 17 sur le poids corporel et la pression artérielle du rat LH. En particulier, il explique presque totalement l hypertriglycéridémie spontanée de ce modèle. Quant au chromosome 13, il est un déterminant majeur de l hypertension, de la protéinurie et de l hyperlipidémie du rat LH, et ce sans changement de l activité rénine plasmatique. En conclusion, la création de ces souches consomiques a précisé sur le plan fonctionnel les données de l analyse de liaison. Elle constitue une base pour générer des souches congéniques chevauchantes qui devraient permettre l approche des gènes impliqués dans l hypertension du rat LHEssential hypertension is a multifactorial disease resulting from the interaction between genetic and environmental factors that are, mostly, unknown. Genetically hypertensive rats of the Lyon strain (LH) associate high blood pressure and signs of metabolic syndrome (overweight, spontaneous hyperlipidemia and increased insulin-to-glucose plasma ratio). A genetic mapping study in 2nd generation hybrids derived from a cross between LH and Lyon Normotensive (LN) showed the existence of quantitative trait loci (QTLs) influencing blood pressure on chromosome 13 and 17. In order to determine the functional importance of these chromosomes, we substituted, in LH rats each of them by the corresponding chromosome from normotensive Brown Norway (BN) rats. These consomic strains and the parental strains (LH and BN) were carefully phenotyped. This work showed the influence of chromosome 17 on body weight and blood pressure of LH rats. In addition, chromosome 17 appeared to explain quasi totally the spontaneous hypertriglyceridemia of this model. Chromosome 13 was demonstrated to be a major determinant of hypertension, proteinuria and hyperlipidemia in LH rats, independently of any change in plasma renin activity. In conclusion, these consomic strains were useful to evaluate the functional importance of the QTLs identified by the linkage analysis. They also constitute a good basis for the generation of the multiple overlapping congenic strains which are necessary to focus on the genes involved in the hypertension of the LH ratLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis*

Scavenger receptor SR-BI significantly contributes to HDL cholesterol metabolism and atherogenesis in mice. However, the role of SR-BI may not be as pronounced in humans due to cholesteryl ester transfer protein (CETP) activity. To address the impact of CETP expression on the adverse effects associated with SR-BI deficiency, we cross-bred our SR-BI conditional knock-out mouse model with CETP transgenic mice. CETP almost completely restored the abnormal HDL-C distribution in SR-BI-deficient mice. However, it did not normalize the elevated plasma free to total cholesterol ratio characteristic of hepatic SR-BI deficiency. Red blood cell and platelet count abnormalities observed in mice liver deficient for SR-BI were partially restored by CETP, but the elevated erythrocyte cholesterol to phopholipid ratio remained unchanged. Complete deletion of SR-BI was associated with diminished adrenal cholesterol stores, whereas hepatic SR-BI deficiency resulted in a significant increase in adrenal gland cholesterol content. In both mouse models, CETP had no impact on adrenal cholesterol metabolism. In diet-induced atherosclerosis studies, hepatic SR-BI deficiency accelerated aortic lipid lesion formation in both CETP-expressing (4-fold) and non-CETP-expressing (8-fold) mice when compared with controls. Impaired macrophage to feces reverse cholesterol transport in mice deficient for SR-BI in liver, which was not corrected by CETP, most likely contributed by such an increase in atherosclerosis susceptibility. Finally, comparison of the atherosclerosis burden in SR-BI liver-deficient and fully deficient mice demonstrated that SR-BI exerted an atheroprotective activity in extra-hepatic tissues whether CETP was present or not. These findings support the contention that the SR-BI pathway contributes in unique ways to cholesterol metabolism and atherosclerosis susceptibility even in the presence of CETP

Evaluation of the efficiency of hydroxychloroquine in treating children with immune thrombocytopenia (ITP)

International audienc

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

International audienc

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Ppar expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPAR expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesit

Molecular and clinicopathologic characterization of pediatric histiocytoses

Molecular and clinicopathologic characterization of pediatric histiocytoses

Molecular and clinicopathologic characterization of pediatric histiocytoses

International audienceThe spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E. Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E-mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches