A novel mechanism for ART-associated dyslipidemia and atherosclerosis

 描述（由申请人提供）：由于在过去几十年中引入了有效的抗逆转录病毒疗法（ART），艾滋病毒长期存活率的提高使人们对艾滋病毒感染的后遗症和用于治疗艾滋病毒患者的疗法产生了新的认识。与HIV感染和抗逆转录病毒（ARV）药物治疗相关的合并症的累积证据包括显著的血脂异常和发生动脉粥样硬化性心血管疾病（CVD）的风险升高。本项目的目的是研究ART相关血脂异常和心血管疾病（CVD）的新机制。几种抗逆转录病毒药物已被确定为对β-内酰胺X受体（PXR）有效的激动剂，PXR是一种由许多药物、异生物质和膳食化学品激活的核受体。PXR作为异生物质传感器，诱导肝脏和肠道中异生物质代谢所需的基因表达。在过去的十年中，PXR在药物和异生物质代谢的调节中的功能已经被许多实验室广泛研究，并且PXR作为异生物质传感器的作用已经被很好地建立。我们最近在动物模型中揭示了PXR的促动脉粥样硬化作用，并证明慢性PXR激活诱导野生型小鼠高脂血症，并增加动脉粥样硬化倾向载脂蛋白E缺陷（ApoE-/-）小鼠的动脉粥样硬化。初步研究表明，HIV蛋白酶抑制剂安普那韦可激活PXR，并在野生型小鼠中诱导高脂血症，但在PXR缺陷型小鼠中不诱导高脂血症;随后对目前使用的一线抗逆转录病毒药物的跟踪研究发现，这些药物可激活PXR，并诱导PXR介导的基因表达。该项目的目标是对ART相关血脂异常和CVD风险产生新的机制见解。我们的中心假设是，长期使用激活PXR的抗逆转录病毒药物治疗将导致脂质稳态异常和加速动脉粥样硬化。我们提出了以下具体目标来验证这一假设：1）确定PXR对目前推荐的ARV药物对脂质稳态的不良影响的贡献; 2）定义PXR激动性ARV药物诱导高脂血症的分子机制; 3）确定ARV药物介导的PXR激活对巨噬细胞功能和动脉粥样硬化发展的影响。这些研究将为ART相关血脂异常和CVD风险提供关键的机制见解和新的理解，并将对接受PXR激动剂药物长期治疗的患者产生直接的临床后果。

 DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR), a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade, the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore, follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.