Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Several proto-oncogenes that encode nuclear proteins are activated by various chromosomal translocations in ALL including TALI, TAL2, and LMO1 and LMO2. Ectopic TALI expression is observed in about 50 % of T-ALL and is the most common genetic anomaly associated with this pathology. Of interest to the present work is the characterization of various multiprotein complexes and protein protein interactions that drive T-ALL progression (as it relates to TALI and LMO1) and over expression of TALI and LMO1 has been shown to have inhibitory effects on apoptosis. Recent data suggests possible interactions between these two oncoproteins and the protein product of the lipoprotein lipase (LPL) gene. Lipoprotein lipase has a complex pattern of regulation and can be regulated in different ways including down-regulation upon induction of TNF-a in 3T3-L1 cells. Thus, this study was undertaken to determine if LPL is expressed in cells over expressing TAL1 and LMO1. Results from this study demonstrated an increase in LPL expression at both transcriptional and translational level in cells engineered to express TAL1 alone and TAL1 and LMO1 together. This finding is a step forward to understanding mechanisms that result in apoptosis prevention in T-ALL. Therefore, the apoptosis preventive role seen in cells that over express TAL and LMO1 and the presence of LPL in the same cell line, theorizes an apoptosis preventive role for lipoprotein lipase as well. / Department of Physiology and Health Science

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1991. / "Mémoire présenté pour l'obtention du grade de maître en sciences (M.Sc.)" Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise en médecine expérimentale (volet génétique) extensionné de l'Un. Laval à l'UQAC. CaQCU CaQCU Bibliogr.: f. 82-86. Document électronique également accessible en format PDF. CaQCU

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21959号 / 医博第4501号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 小杉 眞司, 教授 長船 健二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Increased triglyceride (TG) concentration has been generally accepted as a risk factor for ischemic heart disease and, therefore, lowering TG is therapeutic target that should reduce cardiovascular disease risk. Traditionally, concentration of TG is measured in the fasting state (8-12 hours after an overnight fasting) mainly because the rise in TG levels after meal leads to the high variation in TG values. However, human beings spend larger portion of the day in a postprandial state and postprandial hypertriglyceridemia may then play a substantial role in determination of cardiovascular disease risk. The increased and prolonged postprandial lipemia has been found in patients with coronary heart disease. Moreover, recent data from Copenhagen Heart Study point out that the non-fasting TG concentration is associated with cardiovascular disease risk more tightly than the fasting TG concentration. Importantly, concentration of non-fasting TG is substantially affected by individual behavioural habits such as diet composition and physical activity. It remains to be determined whether it would be appropriate to identify individuals at higher risk of cardiovascular disease due to increased postprandial TG using tolerance test analogous to glucose tolerance test. The protocol of standardized fat tolerance...

The regulation of the serum triglyceride responses to fat ingestion have been examined in normolipidemic men. To evaluate the existing methods for comparing chylomicron-triglyceride clearance, the oral and intravenous fat tolerance tests and a steady state duodenal perfusion method were compared. Good correlations (r > 0.8) were found between each of these methods. Since the intravenous fat tolerance test is independent of fat absorption, these data suggested that the serum triglyceride response to fat feeding was largely determined by the rate of chylomicron-triglyceride clearance. To determine the influence of the quantity and type of meal fat on postprandial serum triglyceride concentrations, the serum triglyceride responses to three different doses of dairy cream, and to standard doses of olive and sunflower oil were examined. For a given type of fat, the magnitude of postprandial lipemia (the integrated serum triglyceride excursion) varied directly with the quantity of fat in the meal. This finding suggested that the chylomicron- triglyceride clearance system(s) did not become saturated even after large fat meals. In addition, it appeared that the hormonal factors released in response to fat ingestion (some of which are known to increase lipoprotein lipase activity in vitro) did not increase the rate of chylomicron-triglyceride clearance. If the quantity of fat in a meal was fixed, then postprandial lipemia increased with increasing saturation of the triglyceride fatty acids. These differences did not appear to reflect differences in triglyceride absorption. Since acute fat feeding per se did not appear to stimulate chylomicron-triglyceride clearance, the effects of dietary proteins and carbohydrates were studied. The addition of up to 35g protein to a standard test meal did not affect postprandial lipemia. These results were supported by the observation that protein ingestion did not affect intravenous fat tolerance. Postprandial serum triglyceride concentrations were significantly influenced by carbohydrate ingestion. Fructose (50g) and sucrose (100g) markedly increased postprandial lipemia, although glucose ingestion did not. In agreement with earlier studies, glucose ingestion decreased serum triglyceride concentrations 2 hours after the meal. This effect was abolished by intraduodenal fat administration and by substituting starch for glucose in the test meal. The effects of glucose could be reproduced by iso-osmotic quantities of urea, however. These findings suggested that glucose ingestion did not increase chylomicron -triglyceride clearance. It is more likely that glucose delayed the absorption of triglycerides by slowing gastric emptying, and that this effect was partly related to the increased osmolarity of glucose- containing meals. The effects of chronic exercise on postprandial lipemia and chylomicron-triglyceride clearance were determined in endurance- adapted athletes. The serum triglyceride responses to large and small fat meals were lower in athletes than in sedentary men with comparable fasting triglyceride concentrations. These differences were not eliminated by a single bout of acute exercise in the sedentary men. The clearance of intravenously administered lntralipid, and chylomicron -triglyceride clearance assessed from steady state chylomicron-triglyceride concentrations during duodenal fat perfusion were faster in athletes than in the sedentary men. These data suggested that the low postprandial lipemia in athletes reflects increased chylomicron-triglyceride clearance caused by increased activity of the triglyceride clearing system(s). Given these considerations. it appears that the pathway(s) for chylomicron triglyceride clearance are extremely efficient in normal men and that these pathways are not subject to acute physiological regulation.

Emulsões artificiais sem proteína simulando quilomicrons e remanescentes de quilomícron foram preparadas por sonicalcação de trioleína, lecitina, colesteril oleato e colesterol em solução aquosa. A seguir foram ultracentrifugadas em gradiente descontínuo de densidade. As emulsões, marcadas com 3H-trioleína e 14C-colesteril oleato foram injetadas via intra-arterial em ratos controle e em ratos tratados com Triton WR1339, sulfato de protamina e heparina, medindo-se a seguir a remoção plasmática do colesteril-ester e dos triglicérides, durante dez minutos. O Triton WR 1339 e a protamina inibiram a lipólise dos quilomícrons artificiais, diminuindo a remoção destas partículas do plasma. O Triton WR 1339 mostrou ser mais efetivo que a protamina nestes efeitos. Por outro lado, a heparina promoveu uma lipólise rápida e brusca nos quilomícrons artificiais, assim como uma aceleração na remoção destas partículas do plasma. Em contraste flagrante com esses resultados, o metabolismo dos remanescentes de quilomícron não foi consideravelmente afetado pelo tratamento com Triton e heparina. Estas experiências indicam que as emulsões artificiais reproduzem o comportamento metabólico dos quilomícrons e remanescentes de quilomícron naturais, em condições em que a atividade da lipase lipoproteica esteja alterada. / Protein-free emulsions models of chylomicrons and chylomicron remnants were prepared by sonicating triolein, lecithin., cholesteryl oleate and cholesterol in aqueous saline media, followed by ultracentrifugation in density gradient solution. The 3H-triolein and 14C-cholesteryl oleate labeled emulsions were injected into the carotid artery of control rats and rats treated with Triton WR 1339, protamine sulphate and heparin. Plasma removal of both labels was measured during ten minutes in two minutes intervals. Triton WR 1339 and protamine sulphate strongly inhibited lipolysis of chylomicron-like emulsions leading to delayed removal of the particles from blood. Triton WR 1339 de appeared to be more effective than protamine to elicit these effects. On the other hand, heparin produced instantaneous lipolysis of the chylomicron-like particles markedly enhancing its removal from plasma. Contrarily, chylomicron remnant-like emulsions were not considerably affected either by Triton WR 1339 or by heparin treatment. The above described results obtained with artificial emulsions support current concepts on the metabolic behavior of natural chylomicron and remnant submitted to changes in lipoprotein lipase action.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [83]-113).