PROTEASE INHIBITOR RELATED DYSLIPIDEMIA

蛋白酶抑制剂用于HIV患者的治疗，已有报道导致血浆甘油三酯、胆固醇和血糖升高，但很少会导致严重的高甘油三酯血症、胰腺炎和糖尿病，并伴有胰岛素抵抗、过度脂肪沉积和脂肪营养不良。我们的目标是测定空腹血清胆固醇(C)、甘油三酯(TG)、残余脂蛋白(RLP)C和甘油三酯(TG)、低密度脂蛋白(LDL)C、高密度脂蛋白C、脂蛋白(A)、载脂蛋白A-I和B、载脂蛋白E、同型半胱氨酸、游离脂肪酸、血糖、胰岛素和血压。我们还将在400名正在接受营养状况评估并正在服用包括蛋白酶抑制剂在内的各种抗病毒药物的前瞻性队列中，通过超声波评估吸烟状况、颈动脉壁厚度以及通过计算机断层扫描评估冠状动脉钙化。将对使用和不使用抑制剂以及纵向和对照进行比较。我们的对照组是弗雷明翰后代研究的参与者，他们接受了所有相同的参数测量(n=3250)。服用蛋白酶抑制剂导致高脂血症的HIV患者将接受吉非罗齐或阿托伐他汀治疗。我们还将检测在添加或不添加脂肪酸和胆固醇的情况下，对Hep G2和CaCo2细胞中的蛋白酶抑制对脂蛋白组装和分泌以及载脂蛋白、低密度脂蛋白受体和微粒体转移蛋白(MTP)基因表达的影响。抑制蛋白酶对脂蛋白代谢和主动脉泡沫细胞形成的影响也将在F1B仓鼠的食物和高胆固醇和饱和脂肪的饮食中进行评估。此外，在有或没有利托那韦抑制的情况下，通过GC/MS分析和多室模拟，在持续进食状态下，使用预充液和去氢亮氨酸，将测定10名男性和10名女性HIV患者脂蛋白中apoB-48和apoB-100的分泌和分解代谢。我们将检验以下假设：1)蛋白酶抑制剂通过增加RLP而增加甘油三酯和胆固醇；2)RLP增加导致颈动脉壁厚度增加和冠状动脉钙化；3)这些增加可以通过饮食、吉非罗齐和/或阿托伐他汀治疗得到改善；4)在细胞培养中，这些RLP增加与apo B-100的分泌增加有关，因为细胞内降解减少，细胞脂质含量增加；5)在金黄地鼠，在致动脉粥样硬化的饮食的动物中，RLP增加，特别是在蛋白酶抑制的情况下，这导致主动脉泡沫细胞的形成增加；6)在人类中，蛋白酶抑制导致富含甘油三酯的脂蛋白apo B-100的分泌增加。这项研究应该明确问题的性质，其机制，以及针对HIV患者蛋白酶抑制剂引起的高脂血症的治疗方法。

Protease inhibitors are used as therapy in HIV patients and have been reported to cause elevations in plasma triglycerides, cholesterol, and glucose, and rarely to induce severe hypertriglyceridemia, pancreatitis, and diabetes mellitus with insulin resistance, excess fat deposition, and lipodystrophy. Our aims are to measure fasting Serum cholesterol (C), triglyceride (TG), remnant lipoprotein (RLP) C and TG, low density lipoprotein (LDL) C, high density lipoprotein C, lipoprotein(a), apolipoproteins A-I and B, apo E genotype, homocysteine, free fatty acids, glucose, insulin, and blood pressure. We will also assess smoking status, carotid artery wall thickness by ultrasound, and coronary artery calcification by computerized tomography in our prospective cohort of 400 HIV patients whose nutritional status is being evaluated and who are taking a variety of antiviral agents including protease inhibitors. Comparisons will be made on and off inhibitors and also longitudinally, and with controls. Our comparison group are participants in the Framingham Offspring Study who have had all the same parameters measured (n=3250). HIV patients who become hyperlipidemic on protease inhibitors will be treated with either gemfibrozil or atorvastatin. We will also examine the effects of protease inhibition in Hep G2 and CaCo2 cells with or without supplementation with fatty acids and cholesterol on lipoprotein assembly and secretion and apolipoprotein, LDL receptor, and microsomal transfer protein (MTP) gene expression. The effects of protease inhibition on lipoprotein metabolism and aortic foam cell formation will also be assessed in F1B hamsters on chow and on diets high in cholesterol and saturated fat. In addition, using a primed constant infusion in the constantly fed state and deuterated leucine, the secretion and catabolism of apoB-48 and apoB-100 within lipoproteins will be determined by GC/MS analysis and multicompartmental modeling in the presence or absence of protease inhibition with ritonavir in 10 males and 10 female HIV patients. We will test the following hypothesis: 1) protease inhibitors increase triglyceride and cholesterol by increasing RLP; 2) elevated RLP leads to increased carotid wall thickness and coronary calcification; 3) these increases can be ameliorated with diet, gemfibrozil and/or atorvastatin treatment; 4) in cell culture these RLP increases are elated to enhanced secretion of apo B-100 due to less intracellular degradation, and excess cellular lipid content; 5) in hamsters there are increased RLP in serum in animals on the atherogenic diet, especially with protease inhibition, and this leads to increased aortic foam cell formation; 6) in humans protease inhibition causes increased triglyceride-rich lipoprotein apo B-100 secretion. This research should define the nature of the problem, its mechanism, and methods for treatment wit regard to the hyperlipidemia induced by protease inhibitors in HIV patients.