PROTEASE INHIBITOR RELATED DYSLIPIDEMIA

蛋白酶抑制剂被用作HIV患者的治疗药物，据报道可导致血浆甘油三酯、胆固醇和葡萄糖升高，很少会诱导重度高甘油三酯血症、胰腺炎和糖尿病伴胰岛素抵抗、过量脂肪沉积和脂肪代谢障碍。检测空腹血清胆固醇（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、血糖、胰岛素和血压。 我们还将评估400名HIV患者的吸烟状况、超声检查颈动脉壁厚度和计算机断层扫描检查冠状动脉钙化，这些患者的营养状况正在接受评估，并且正在服用各种抗病毒药物，包括蛋白酶抑制剂。 将进行有无抑制剂的比较以及纵向比较，并与对照组进行比较。 我们的对照组是Frachial Offspring研究的参与者，他们测量了所有相同的参数（n=3250）。 使用蛋白酶抑制剂后出现高血脂的HIV患者将接受吉非罗齐或阿托伐他汀治疗。 我们还将研究蛋白酶抑制在Hep G2和CaCo 2细胞中的作用，有或没有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受体和微粒体转移蛋白（MTP）基因表达的影响。 还将在进食食物和高胆固醇和饱和脂肪饮食的F1 B仓鼠中评估蛋白酶抑制对脂蛋白代谢和主动脉泡沫细胞形成的影响。 此外，在10名男性和10名女性HIV患者中，在存在或不存在利托那韦蛋白酶抑制的情况下，使用持续进食状态下的预充恒定输注和氘代亮氨酸，通过GC/MS分析和多房室模型确定脂蛋白内apoB-48和apoB-100的分泌和催化。 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、吉非罗齐和/或阿托伐他汀治疗来改善; 4）在细胞培养中，这些RLP的增加与由于较少的细胞内降解和过量的细胞脂质含量导致的apo B-100分泌增加有关; 5）在仓鼠中，在致动脉粥样硬化饮食的动物中，特别是在蛋白酶抑制的情况下，血清中RLP增加，这导致主动脉泡沫细胞形成增加; 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分泌增加。 这项研究应明确问题的性质，其机制，并治疗方法与蛋白酶抑制剂引起的高脂血症的艾滋病患者。

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.