Mechanisms of HIV Protease Inhibitor-Induced Lipid Dysregulation in Adipocytes

HIV 蛋白酶抑制剂诱导的脂肪细胞脂质失调的机制

• 批准号: 7806933
• 负责人: Beth S Zha
• 金额: $ 3.24万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806933
• 关键词: Adipocytes; Adipose tissue; Adjuvant Therapy; Adverse effects; Alternative Medicine; Alternative Therapies; Calcium; Cell Culture Techniques; Cells; Cholesterol; Chronic; Chronic Disease; Coculture Techniques; Cytokine Activation; Development; Disease; Dyslipidemias; Endoplasmic Reticulum; Future; HIV; HIV Protease Inhibitors; HIV therapy; Hepatocyte; Highly Active Antiretroviral Therapy; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Laboratories; Learning; Link; Lipids; Lipodystrophy; Messenger RNA; Metabolic Diseases; Methods; Molecular; Morbidity - disease rate; Mus; Onset of illness; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Protease Inhibitor; Proteins; Role; Testing; Treatment Protocols; cytokine; endoplasmic reticulum stress; knock-down; lipid metabolism; macrophage; mortality; novel therapeutics; prevent; public health relevance

DESCRIPTION (provided by applicant): The development of highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients, yet the regimen also often results in chronic metabolic diseases. Dyslipidemia, insulin resistance, and lipodystrophy observed in patients receiving HAART have been linked to HIV protease inhibitors (PI). Previous studies have shown that HIV Pis activate ER stress, which underlies inflammatory responses and dysregulation of lipid metabolism in macrophages and hepatocytes. Within adipocytes, key players in both body lipid storage and inflammation, HIV Pis have been shown to activate ER stress, increase proinflammatory cytokine secretions, alter lipid metabolism, and inhibit differentiation of pre-adipocytes to mature adipocytes. Yet, the cellular mechanisms of HIV Pl-induced dysregulations have not been elucidated. We hypothesize that HIV Pis disrupt lipid metabolism by activating ER stress and inflammatory responses in adipocytes. We will test this hypothesise through three specific aims. AIM 1 is to elucidate the mechanism of HIV Pl-induced ER stress in adipocytes. We will accomplish this by studying protein and mRNA level changes in pre- and differentiated murine, as well as human, cultured adipocytes. AIM 2 is to define the role of ER stress in HIV Pl-induced dysregulation of adipocyte lipid metabolism and induction of the inflammatory response. We will first focus on the effects of HIV Pis in these processes and then knock down key players of the ER stress pathway to test how these effects are altered. Aim 3 is to characterize the contribution of HIV Pl-induced macrophage cytokine secretions play in adipocyte ER stress activation, adipocyte cytokine secretion, and adipose tissue inflammation. We will treat co-cultures of macrophages and adipocytes to analyze differences in UPR activation and cytokine secretions versus cells cultured and treated alone. We will follow this by in vitro studies to determine the extent HIV PI treatment has on adipose tissue inflammation. By understanding how HIV Pis disrupt normal function in key cells of metabolic disease, we can learn to prevent the onset of these diseases by using concurrent alternative therapies with HAART in HIV patients. Public Health Relevance: HAART-induced dylipidemia and lipodystrophy are two major side effects of a pivotal drug regimen used for treating HIV-infected patients. Determining the underlying cellular/molecular mechanisms by which some of these drugs cause devastating metabolic diseases can allow us to develop new therapies that will counteract induction of these chronic illnesses.

描述（由申请人提供）： 高效抗逆转录病毒疗法（HAART）的发展显着降低了艾滋病毒感染者的发病率和死亡率，但该疗法也常常导致慢性代谢性疾病。 在接受HAART的患者中观察到的血脂异常、胰岛素抵抗和脂肪营养不良与HIV蛋白酶抑制剂(PI)有关。先前的研究表明，HIV Pis 会激活内质网应激，而内质网应激是巨噬细胞和肝细胞炎症反应和脂质代谢失调的基础。在脂肪细胞（体内脂质储存和炎症的关键参与者）中，HIV Pis已被证明可以激活内质网应激，增加促炎细胞因子的分泌，改变脂质代谢，并抑制前脂肪细胞向成熟脂肪细胞的分化。然而，HIV P1诱导的失调的细胞机制尚未阐明。我们假设 HIV Pis 通过激活脂肪细胞中的内质网应激和炎症反应来破坏脂质代谢。我们将通过三个具体目标来检验这一假设。目的1是阐明HIV P1诱导脂肪细胞内质网应激的机制。我们将通过研究预分化和分化的小鼠以及人类培养的脂肪细胞中蛋白质和 mRNA 水平的变化来实现这一目标。目的2是确定ER应激在HIV P1诱导的脂肪细胞脂质代谢失调和炎症反应诱导中的作用。我们将首先关注 HIV Pis 在这些过程中的影响，然后敲除 ER 应激途径的关键参与者，以测试这些影响是如何改变的。目标3是表征HIV P1诱导的巨噬细胞细胞因子分泌在脂肪细胞ER应激激活、脂肪细胞细胞因子分泌和脂肪组织炎症中的作用。我们将处理巨噬细胞和脂肪细胞的共培养物，以分析与单独培养和处理的细胞相比，UPR 激活和细胞因子分泌的差异。我们将通过体外研究来确定 HIV PI 治疗对脂肪组织炎症的影响程度。通过了解 HIV Pis 如何破坏代谢疾病关键细胞的正常功能，我们可以学习通过在 HIV 患者中同时使用 HAART 替代疗法来预防这些疾病的发生。 公共卫生相关性：HAART 引起的血脂异常和脂肪代谢障碍是治疗的两个主要副作用。 用于治疗 HIV 感染患者的关键药物治疗方案。确定其中一些药物引起破坏性代谢疾病的潜在细胞/分子机制可以使我们开发出新的疗法来抵消这些慢性疾病的诱发。