A novel mechanism for ART-associated dyslipidemia and atherosclerosis

 描述(申请人提供)：由于过去几十年采用有效的抗逆转录病毒疗法(ART)而导致的艾滋病毒长期存活率的上升，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。越来越多的证据表明，与艾滋病毒感染和抗逆转录病毒(ARV)药物治疗相关的共病包括显著的血脂异常和发展为动脉粥样硬化性心血管疾病(CVD)的风险增加。该项目的目标是研究ART相关血脂异常和心血管疾病(CVD)的新机制。几种ARV药物已被确定为孕烷X受体(PXR)的有效激动剂，PXR是一种核受体，可被多种药物、异物和饮食化学品激活。PXR是一种异生感受器，可诱导肝脏和肠道中异生代谢所需基因的表达。在过去的十年里，PXR在药物和异种生物代谢调节中的作用已经被许多实验室广泛研究，并且PXR作为异种生物传感器的作用已经得到了很好的证实。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激活会导致野生型小鼠的高脂血症，并增加动脉粥样硬化易患载脂蛋白E缺陷(ApoE-/-)小鼠的动脉粥样硬化。初步研究表明，HIV蛋白水解酶抑制剂氨丙那韦可以激活PXR并诱导野生型小鼠的高脂血症，但在PXR缺陷小鼠中不能；此外，对目前使用的一线抗逆转录病毒药物的后续研究随后发现，这些药物激活PXR并诱导PXR介导的基因表达。这个项目的目标是对与ART相关的血脂异常和心血管疾病风险产生新的机械性见解。我们的中心假设是，长期使用激活PXR的ARV药物治疗将导致异常的脂平衡和加速的动脉粥样硬化。我们提出以下具体目的来验证这一假说：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)确定PXR激动型ARV药物诱导高脂血症的分子机制；以及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。这些研究将提供关键的机制见解和对ART相关血脂异常和心血管疾病风险的新理解，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.