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

描述（由申请人提供）：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，但预期寿命的提高与一部分患者的一系列复杂代谢紊乱有关。这些疾病包括生长衰竭和低瘦体重（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。为了建立儿科患者的新疗法，阐明这些机制是很重要的，因为生长衰竭会导致发育迟缓，而慢性血脂异常可能会加速成年期心血管疾病的进展。在这个项目中，我们计划测试以下假设：1) hiv感染伴血脂异常患者的高甘油三酯血症是极低密度脂蛋白（VLDL）合成速率增加的结果，继发于禁食状态下脂肪分解速度加快，而VLDL-和乳糜微粒- tg的水解受损，继发于进食状态下脂蛋白脂肪酶活性受损。2)高胆固醇血症部分是由于高密度脂蛋白载脂蛋白Al （HDL-apoAl）可用性降低导致胆固醇转运到肝脏受损；3)富含多不饱和脂肪酸和单不饱和脂肪酸的低脂饮食将改善hiv感染的血脂异常受试者的高甘油三酯血症和高胆固醇血症。关于蛋白质代谢，我们假设4)感染艾滋病毒的儿童由于蛋白质分解代谢上调而导致净蛋白质合成缺陷，因此LBM较低。为了验证这些假设，我们建议进行稳定同位素示踪剂实验，以实现以下具体目标：通过DEXA、血浆脂质谱、空腹和进食状态下血浆脂肪酸出现率、脂肪酸氧化、肝脏脂肪酸再酯化、HDL-apoAl、VLDL-TG和- apoB-100的浓度和合成率以及脂蛋白脂肪酶活性测量患有血脂异常的hiv感染青少年组与无血脂异常的匹配组的身体组成。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低脂饮食（28%能量）与不改变饮食对患有血脂异常的艾滋病毒感染青少年这些相同结果变量的影响。具体目标#3。测量hiv感染的青春期前儿童与年龄和性别匹配的hiv暴露儿童的瘦体重（LBM）和蛋白质动力学，并确定饮食能量和蛋白质补充对hiv感染组的LBM和蛋白质动力学的影响。这项研究可以解释为什么感染艾滋病毒的儿科患者不能正常生长，为什么他们的血液中脂肪和胆固醇含量高，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.