PROTEASE INHIBITOR RELATED DYSLIPIDEMIA

蛋白酶抑制剂相关的血脂异常

• 批准号: 6215535
• 负责人: Christine A Wanke
• 金额: $ 54.28万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-12 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6215535
• 关键词: AIDS therapy; HIV infections; antihyperlipoproteinemic agent; apolipoprotein B; atherosclerosis; blood chemistry; blood lipoprotein; blood lipoprotein metabolism; cholesterol; clinical research; cooperative study; diet therapy; dietary lipid; drug adverse effect; hamsters; human data; human subject; hyperlipidemia; nutrition related tag; protease inhibitor; ritonavir; tissue /cell culture; triglycerides

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.

蛋白酶抑制剂用于治疗 HIV 患者，据报道会导致血浆甘油三酯、胆固醇和葡萄糖升高，但很少会诱发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、过量脂肪沉积和脂肪营养不良。我们的目标是测量空腹血清胆固醇 (C)、甘油三酯 (TG)、残余脂蛋白 (RLP) C 和 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基因型、同型半胱氨酸、游离脂肪酸、葡萄糖、胰岛素和血压。 我们还将评估 400 名 HIV 患者的前瞻性队列中的吸烟状况、超声颈动脉壁厚度和计算机断层扫描冠状动脉钙化情况，这些患者的营养状况正在接受评估，并且正在服用包括蛋白酶抑制剂在内的各种抗病毒药物。 将在使用和不使用抑制剂的情况下进行比较，并与对照组进行纵向比较。 我们的对照组是 Framingham 后代研究的参与者，他们测量了所有相同的参数 (n=3250)。 服用蛋白酶抑制剂后出现高脂血症的艾滋病毒患者将接受吉非贝齐或阿托伐他汀治疗。 我们还将研究补充或不补充脂肪酸和胆固醇的 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、LDL 受体和微粒体转移蛋白 (MTP) 基因表达的影响。 蛋白酶抑制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饮食中进行评估。 此外，在持续进食状态下使用引发的恒定输注和氘化亮氨酸，在存在或不存在蛋白酶抑制的情况下，将通过 GC/MS 分析和多室模型确定脂蛋白内 apoB-48 和 apoB-100 的分泌和分解代谢对 10 名男性和 10 名女性 HIV 患者使用利托那韦治疗。 我们将检验以下假设：1）蛋白酶抑制剂通过增加RLP来增加甘油三酯和胆固醇； 2）RLP升高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、吉非贝齐和/或阿托伐他汀治疗来改善； 4) 在细胞培养中，这些 RLP 增加与 apo B-100 分泌增强有关，这是由于细胞内降解较少和细胞脂质含量过多所致； 5) 在仓鼠中，采用致动脉粥样硬化饮食的动物血清中的 RLP 增加，特别是在蛋白酶抑制作用下，这导致主动脉泡沫细胞形成增加； 6) 在人体中，蛋白酶抑制会导致富含甘油三酯的脂蛋白apo B-100 分泌增加。 这项研究应明确艾滋病毒患者中蛋白酶抑制剂引起的高脂血症的问题性质、机制和治疗方法。