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

HIV感染儿科患者脂质和蛋白质代谢的改变

• 批准号: 7870417
• 负责人: FAROOK JAHOOR
• 金额: $ 60.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870417
• 关键词: Adolescent; Adult; Age; Apoprotein (B); Apoproteins; Appearance; Blood; Body Composition; Bone Density; Cardiovascular Diseases; Catabolism; Child; Childhood; Cholesterol; Chronic; Chylomicrons; Clinical; Complex; DEXA; Diet; Diet Modification; Dietary Proteins; Dietary Supplementation; Disease; Dyslipidemias; Esterification; Failure; Fasting; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Gender; Growth; HIV; HIV Infections; Heart Diseases; Hepatic; High Density Lipoproteins; Highly Active Antiretroviral Therapy; Hydrolysis; Hypertriglyceridemia; Insulin Resistance; Intake; Kinetics; Knowledge; Lead; Life Expectancy; Lipids; Lipoatrophy; Lipolysis; Literature; Liver; Matched Group; Measures; Metabolic; Metabolic Diseases; Mono-S; Morbidity - disease rate; Nutrition Disorders; Nutritional Support; Obesity; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Protein Biosynthesis; Proteins; Relative (related person); Research; Risk; Secondary to; Staging; Supplementation; Syndrome; Testing; Tracer; Triglycerides; Unsaturated Fatty Acids; Up-Regulation; Very low density lipoprotein; apolipoprotein B-100; fatty acid oxidation; feeding; hypercholesterolemia; improved; indexing; lipoprotein lipase; mortality; prepuberty; prevent; protein metabolism; research study; reverse cholesterol transport; stable isotope; sterol esterase; young adult

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.

描述（由申请人提供）：尽管高度活跃的抗逆转录病毒疗法（HAART）显着降低了艾滋病毒感染儿童的发病率和死亡率，但预期寿命的改善与一组复杂的代谢疾病有关。这些疾病包括生长衰竭，较低的体重（LBM）和血脂异常，这是一种以高甘油三酸酯血症和高胆固醇血症为特征的综合征。尽管描述了这些代谢障碍的临床特征，但它们的机械基础尚不清楚。描述这些机制是为了为小儿患者建立新疗法非常重要的，因为生长失败会导致发育迟缓，慢性血脂异常可能会加速成年后心血管疾病的发展。 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.关于蛋白质代谢，我们假设4）由于蛋白质分解代谢上调，艾滋病毒感染的儿童的LBM较低。为了检验这些假设，我们建议进行稳定的同位素示踪剂实验以实现以下特定目的：特定目标＃1。通过DEXA，血浆脂质谱，禁食状态和联邦饲养状态中的血浆脂肪酸的外观，脂肪酸氧化，肝脂肪酸的重新酯化，HDL-APOAL，VLDL-TG和-APOB-100的HDL-APOAL的浓度和合成速率，以及与Lipopopase lipopase Antercent of lipopopase Antercent of Hiv-100血脂血症。特定目标＃2。比较降低的脂肪饮食（28％能量）的作用，该饮食由较大的单一和多饱和脂肪酸组成，而在患有血脂异常的HIV感染的青少年中，对这些相同结果变量的饮食变量没有饮食改性。特定目标＃3。在HIV感染的青春期前儿童与年龄与性别匹配的HIV暴露儿童中测量瘦体重（LBM）和蛋白质动力学，并确定饮食能量和蛋白质补充对LBM和蛋白质动力学对HIV感染的组的影响。这项研究可能解释了为什么感染HIV的儿科患者无法正常生长，以及为什么他们的血液中会产生高水平的脂肪和胆固醇，这可能会导致早期心脏病。从该项目中获得的知识可能会导致新的营养疗法，以帮助防止这些疾病。