PROTEASE INHIBITOR RELATED DYSLIPIDEMIA

蛋白酶抑制剂相关的血脂异常

• 批准号: 6779193
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779193
• 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; 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.

蛋白酶抑制剂被用作HIV患者的治疗，据报道会导致血浆甘油三酸酯，胆固醇和葡萄糖的升高，很少诱导严重的高糖性血症，胰腺炎和糖尿病，并具有胰岛素抵抗，过量的脂肪降低和脂肪症。 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,胰岛素和血压。 我们还将通过计算机断层扫描评估吸烟状况，颈动脉壁的厚度以及冠状动脉钙化，我们在我们的400名HIV患者中，通过评估营养状况并采用包括蛋白酶抑制剂在内的各种抗病毒药物的400例HIV患者。 比较将在抑制剂和纵向上进行，并与对照组进行比较。 我们的比较组是弗雷明汉后代研究的参与者，他们的所有相同参数测量了（n = 3250）。 在蛋白酶抑制剂上高脂症的HIV患者将用Gemfibrozil或Atorvastatin治疗。 我们还将检查蛋白酶抑制在HEP G2和CACO2细胞中的影响，或者不补充脂肪酸和胆固醇对脂蛋白组装和分泌以及载脂蛋白，LDL受体以及微粒细胞转移蛋白（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Chow上的F1B仓鼠和胆固醇和饱和脂肪的饮食中进行评估。 此外，使用在不断喂养的状态和氘代亮氨酸中使用启动的恒定输注，脂蛋白中APOB-48和APOB-100的分泌和分解代谢将通过GC/MS分析以及在10名男性和10名雌性HIV患者中蛋白酶抑制的情况下通过GC/MS分析和多班剖面建模来确定。 我们将检验以下假设：1）蛋白酶抑制剂通过增加RLP增加甘油三酸酯和胆固醇； 2）升高的RLP导致颈动脉壁的厚度和冠状动脉钙化增加； 3）这些增加可以通过饮食，吉菲贝罗齐和/或阿托伐他汀治疗来改善； 4）在细胞培养中，由于细胞内降解和过量的细胞脂质含量，这些RLP的增加被兴奋地增强了Apo B-100的分泌。 5）在仓鼠中，动物饮食中的动物血清中的RLP增加，尤其是蛋白酶抑制作用，这导致主动脉泡沫细胞的形成增加。 6）在人类中，蛋白酶抑制作用会增加富含甘油三酸酯的脂蛋白APO B-100分泌。 这项研究应定义问题的性质，其机制和治疗方法，以hiv患者的​​蛋白酶抑制剂诱导的高脂血症。