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International audience; Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-alpha-tocopherol) and alpha-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus alpha-tocopherol acetate by measuring the plasma concentrations of alpha-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and alpha-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; alpha-tocopherol acetate, 11.4%). Plasma concentrations of alpha-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.

Les anomalies du métabolisme des lipoprotéines riches en triglycérides (LRTG), les chylomicrons et les VLDL exposent à des hypocholestérolémies lors d'un défaut de sécrétion et à des hypertriglycéridémies (HTG) majeures entraînant un risque athéromateux et de pancréatites aigües lors de l'altération de leur clairance. Nous avons diagnostiqué des patients présentant un défaut génétique de sécrétion des LRTG au décours de maladie de rétention des chylomicrons, d'abetalipoprotéinémie et d'hypobetalipoprotéinémie homozygote, causées respectivement par des mutations sur les gènes SAR1B, MTTP et APOB. Nous avons étudié le phénotype des 158 patients publiés avec mutation délétère et mis en évidence des différences portant principalement sur la stéatose hépatique, l'insulinorésistance et l'obésité. Nous avons également mis au point une méthode d'évaluation de l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL in vitro, permettant l'exploration phénotypique des patients présentant une HTG sévère. Nous avons mis en évidence des activités LPL augmentées chez des patients présentant pourtant des antécédents d'HTG sévère et des déficits chez des patients ne présentant pas de mutation identifiable du gène LPL, laissant supposer l'existence de facteurs additionnels modulant l'expression ou l'activité de la LPL. Enfin des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides modulent le phénotype. Elles soulèvent l'intérêt de l'exploration simultanée des principaux gènes impliqués dans les dyslipidémies, telle qu'elle sera effectuée par NGS, pour une meilleure compréhension de leur physiopathologie, Abnormal metabolism of triglyceride-rich lipoproteins (LRTG), chylomicrons and VLDL, can result in hypocholesterolemia in case of impaired secretion, or severe hypertriglyceridemia (HTG) and increased risk of atheroma and acute pancreatitis if clearance is affected. We explored patients suffering from genetic defect in the LRTG secretion (chylomicron retention disease, abetalipoproteinemia and homozygous hypobetalipoproteinemia) and identified mutations on respectively SAR1B, and MTTP and APOB gene. Then, we analysed the phenotype of 158 previously published patients with deleterious mutation (i.e. reported cases added to our cohort) and were able to highlight some specific differences like hepatic steatosis, insulin resistance and obesity. Furthermore we developed an assay to evaluate the lipoprotein lipase (LPL) functionality by measuring the triglyceride-VLDL lipolysis in vitro, and provide a reliable phenotypic exploration for patients with past history of severe hypertriglyceridemia. We found an increased LPL activity in some patients with severe hypertriglyceridemia but conversely showed deficits in other patients free from mutation on LPL gene. These results lead to hypothesize that additional factors might contribute to modulate the expression or the activity of LPL. Finally multiple genes of triglycerides metabolism interact together to additionally modulate phenotype. Of high interest is therefore the simultaneous exploration of the key genes involved in dyslipidemia, as provided by the new generation sequencing (NGS), for better understanding of all pathophysiological mechanisms

The aim of this thesis is to summarize current knowledge about VLDL (very low density lipoprotein) assembly. In the first part of this thesis basic characteristics of lipids and lipoproteins are described. Lipids are the most favourable source of energy for animals. Lipoproteins are the macromolecular complexes that transport hydrofobic lipids in plasma. According to their density, they are classified to five groups: chylomicrons, VLDL, IDL, LDL, HDL. Second part of this thesis is focused on the apolipoproteins - structural peptide components of lipoproteins. The characteristics and functions of major apolipoprotein classes are explained with the main focus on apolipoproteins B that have an important role in VLDL assembly. The process of VLDL assembly is described in detail in the third part of the thesis. VLDL assembly consists of two steps. Pre-VLDL and lipid droplet are synthetized independently in the first step, for which apolipoprotein B-100 and microsomal triglyceride transfer protein (MTP) are essential. Second step is the fusion of pre-VLDL with the lipid droplet. ADP-ribosylation factor 1 (ARF1) and phospholipase D (PLD) are the essential components in the second step. Also apolipoprotein E, apolipoprotein A-V and acyl-coenzym A:cholesterol acyl transferasa 2 (ACAT2) are important. VLDL...

Diplôme : Dr. d'Universite