The altered lipid and protein metabolism of pediatric patients with HIV infection

描述(申请人提供)：尽管高效抗逆转录病毒疗法(HAART)显著降低了艾滋病毒感染儿童的发病率和死亡率，但预期寿命的延长与部分患者的一系列复杂的代谢紊乱有关。这些疾病包括生长障碍和低瘦体重(LBM)和血脂异常，这是一种以高甘油三酯血症和高胆固醇血症为特征的综合征。虽然这些代谢紊乱的临床特征已被描述，但其机制基础尚不清楚。阐明这些机制对于为儿科患者建立新的治疗方法是很重要的，因为生长障碍会导致发育迟缓，而慢性血脂异常可能会在成年后加速进展为心血管疾病。在这个项目中，我们计划测试以下假设：1)HIV感染患者的高甘油三酯血症是极低密度脂蛋白(VLDL)合成速度增加的结果，其次是禁食状态下更快的脂解速度，以及VLDL-和乳清蛋白-TG的水解度受损，继而是进食状态下脂蛋白脂酶活性受损；2)高胆固醇血症部分是由于高密度脂蛋白载脂蛋白A1(高密度脂蛋白载脂蛋白A1)的可获得性减少而导致胆固醇向肝脏的运输受损，3)富含多不饱和脂肪酸和单不饱和脂肪酸的低脂饮食可改善HIV感染者的高甘油三酯血症和高胆固醇血症。在蛋白质代谢方面，我们假设感染了HIV的儿童由于蛋白质分解代谢上调导致净蛋白质合成不足，所以LBM较低。为了验证这些假设，我们提议进行稳定同位素示踪实验，以实现下列特定目标：特定目标#1.与对照组相比，患有血脂异常的HIV感染青少年组的身体成分、血脂谱、空腹和进食状态下的血浆脂肪酸出现率、脂肪酸氧化、肝脏脂肪酸再酯化、高密度脂蛋白-ApoA1、极低密度脂蛋白-甘油三酯和-ApoB-100的浓度和合成速率，以及脂蛋白脂酶活性。具体目标2：比较由更大比例的单不饱和脂肪酸和多不饱和脂肪酸组成的减脂饮食(28%能量)和不改变饮食对HIV感染的患有血脂异常的青少年的这些结果变量的影响。具体目标#3.测量感染艾滋病毒的青春期前儿童与年龄和性别相匹配的暴露于艾滋病毒的儿童的瘦体重(LBM)和蛋白质动力学，并确定补充饮食能量和蛋白质对HIV感染者组LBM和蛋白质动力学的影响。这项研究可能解释为什么感染艾滋病毒的儿科患者无法正常生长，以及为什么他们的血液中会出现高水平的脂肪和胆固醇，这可能会导致早期心脏病。从这个项目中获得的知识可能会导致新的营养疗法来帮助预防这些疾病。

DESCRIPTION (provided by applicant): Although highly active anti-retroviral therapy (HAART) has markedly reduced the morbidity and mortality of HIV- infected children, the improved life expectancy is associated with a complex set of metabolic disorders in a subset of patients. These disorders include growth failure with lower lean body mass (LBM) and dyslipidemia, a syndrome characterized by hypertriglyceridemia and hypercholesterolemia. Although the clinical features of these metabolic derangements are described, their mechanistic underpinnings are unknown. It is important to delineate these mechanisms in order to establish new therapies for pediatric patients because growth failure will lead to stunting and chronic dyslipidemia may accelerate the progression to cardiovascular disease in adulthood. In this project we plan to test the following hypotheses: 1) the hypertriglyceridemia of HIV-infected patients with dyslipidemia is the result of an increased rate of very low density lipoprotein (VLDL) synthesis, secondary to a faster rate of lipolysis in the fasted state, and impaired hydrolysis of VLDL- and chylomicron-TG, secondary to impaired lipoprotein lipase activity in the fed state, 2) hypercholesterolemia is in part due to impaired cholesterol transport to the liver because of a reduction in the availability of high density lipoprotein apoprotein Al (HDL-apoAl), 3) a lower fat diet rich in poly and mono- unsaturated fatty acids will improve the hypertriglyceridemia and hypercholesterolemia of HIV-infected dyslipidemic subjects. With respect to protein metabolism we hypothesize that 4) HIV-infected children have a lower LBM due to a deficit in net protein synthesis because of upregulated protein catabolism. To test these hypotheses we propose to conduct stable isotope tracer experiments to achieve the following specific aims: Specific aim #1. Measure body composition by DEXA, plasma lipid profile, plasma fatty acid appearance rate in the fasted and fed states, fatty acid oxidation, hepatic fatty acid re-esterification, the concentration and synthesis rates of HDL-apoAl, VLDL-TG and - apoB-100, and lipoprotein lipase activity in a group of HIV-infected adolescents with dyslipidemia versus a matched group without dyslipidemia. Specific aim #2. Compare the effects of a reduced fat diet (28% energy) comprised of a greater proportion of mono- and poly-unsaturated fatty acids versus no dietary modification on these same outcome variables in HIV-infected adolescents with dyslipidemia. Specific aim #3. Measure lean body mass (LBM) and protein kinetics in HIV-infected prepubertal children versus age-and gender-matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on LBM and protein kinetics in the HIV-infected group. This research may explain why HIV-infected pediatric patients fail to grow normally and why they develop high levels of fat and cholesterol in their blood, which can potentially lead to early heart disease. Knowledge gained from this project may lead to new nutritional therapies to help prevent these conditions.