MECH OF HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY-INDUCED HYPERLIPIDEMIA IN HIV

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。高效抗逆转录病毒疗法(HAART)的使用与包括脂营养不良、血脂异常和胰岛素抵抗在内的长期不良代谢事件有关。本研究的目的是前瞻性地研究HAART诱导的高脂血症的机制，在HIV血清阳性、HAART阴性的男性中，HAART诱导的高脂血症发生在发生坦率脂肪营养不良之前。患者(n=13)的体重、BMI、瘦体重、脂肪百分比、腰围在HAART治疗8周后没有变化。HAART-NA患者的血浆FFA浓度已经高于健康、未经治疗的HIV阴性对照组，前者在HAART治疗8周后进一步升高。与健康的匹配对照组相比，在引入HAART之前和之后，胰岛素对血浆FFA浓度的抑制都受到了损害。HAART后极低密度脂蛋白-载脂蛋白B和极低密度脂蛋白-甘油三酯浓度较正常显著升高。与健康对照组相比，HIV血清阳性个体的VLDL部分分解代谢率和清除率降低了约40%，这一缺陷在HAART后没有得到纠正。HAART后VLDL升高的原因是VLDL-apoB和VLDL-TG分泌接近正常，而VLDL清除受损的情况保持不变。我们得出结论，在HAART病程早期循环VLDL升高是由HAART-NA HIV阳性患者已经存在的VLDL清除受损和HAART介导的VLDL分泌增加共同引起的。这些变化伴随着血浆游离脂肪酸的升高，但在身体成分发生重大变化之前发生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The use of highly active anti-retroviral therapy (HAART) is associated with long-term adverse metabolic events including lipodystrophy, dyslipidemia, and insulin resistance. The purpose of the present study was to prospectively examine the mechanism of HAART-induced hyperlipidemia in HIV-seropositive, HAART-na¿ve men prior to the development of frank lipodystrophy. Patient's (n = 13) weight, BMI, lean mass, and percent fat mass, waist circumference did not change after 8 weeks of treatment with HAART. Plasma FFA concentration was already elevated in HAART-na¿ve patients compared to healthy, untreated, HIV negative control individuals and was further increased after 8 weeks of HAART in the former. Insulin-mediated suppression of plasma FFA concentrations was impaired both prior to and following introduction of HAART, compared to healthy, matched controls. VLDL-apoB and VLDL-TG concentrations rose significantly from normal levels after HAART. Compared to healthy control subjects, VLDL fractional catabolic rate and clearance in HIV-seropositive individuals was reduced by approximately 40%, a defect that was not corrected after HAART. The increase in VLDL after HAART was explained by an increase of VLDL-apoB and VLDL-TG secretion towards normal while the impaired VLDL clearance remained unchanged. We conclude that elevation of circulating VLDL early in the course of HAART is caused by the combination of impaired VLDL clearance already present in HAART-na¿ve HIV-seropositive patients and HAART-mediated increase in VLDL secretion. These changes occur concomitantly with an elevation of plasma free fatty acids but before significant change in body composition.