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

基本信息

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
项目类别：
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

项目摘要

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）：高度活跃的抗逆转录病毒疗法（HAART）的发展显着降低了HIV感染患者的发病率和死亡率，但该治疗方案也经常导致慢性代谢疾病。在接受HAART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激活ER应激，这是巨噬细胞和肝细胞中脂质代谢的炎症反应和失调的基础。在脂肪细胞中，体内脂质储存和炎症的主要参与者已显示HIV PI可激活ER应激，增加促炎性细胞因子分泌，改变脂质代谢，并抑制脂肪细胞对成熟脂肪细胞的分化。然而，尚未阐明HIV PL诱导的失调的细胞机制。我们假设HIV PI通过激活脂肪细胞中的ER应激和炎症反应来破坏脂质代谢。我们将通过三个特定目标来检验这一假设。目的1是阐明脂肪细胞中HIV PL诱导的ER应激的机制。我们将通过研究前和分化的鼠以及人类培养的脂肪细胞的蛋白质和mRNA水平变化来实现这一目标。目的2是定义ER应激在HIV PL诱导的脂肪细胞脂质代谢失调和炎症反应诱导中的作用。我们将首先关注艾滋病毒PI在这些过程中的影响，然后击倒ER应力途径的关键参与者，以测试如何改变这些效果。目标3是在脂肪细胞ER应激激活，脂肪细胞细胞因子分泌和脂肪组织炎症中表征HIV诱导的巨噬细胞细胞因子分泌物的贡献。我们将处理巨噬细胞和脂肪细胞的共培养，以分析UPR激活和细胞因子分泌的差异与单独培养和治疗的细胞。我们将通过体外研究遵循这一点，以确定HIV PI治疗对脂肪组织炎症的程度。通过了解HIV PI在代谢疾病的关键细胞中如何破坏正常功能，我们可以学会通过使用HAART在HIV患者中使用并发替代疗法来预防这些疾病的发作。公共卫生相关性：HAART引起的二脂血症和脂肪营养不良是两个主要副作用用于治疗HIV感染患者的关键药物方案。确定其中一些药物引起毁灭性代谢性疾病的潜在细胞/分子机制可以使我们开发新的疗法，以抵消这些慢性疾病的诱导。