Role of PXR in drug-elicited cardiovascular disease

项目摘要 抗精神病治疗被广泛用于治疗包括双相情感障碍在内的精神疾病， 精神分裂症和严重抑郁障碍。这些情况加起来影响了超过20%的 人口，通常需要终生服药。非典型抗精神病药物具有优越的治疗作用和 与典型抗精神病药物相比，不良反应减少，但非典型抗精神病药物的使用也 与患者的血脂异常和心血管疾病(CVD)风险增加相关。潜在的 造成这些不利影响的机制在很大程度上仍不清楚，这会对健康造成严重影响 长期接受抗精神病药物治疗的患者面临的挑战。为此，我们最近确定了几个 非典型抗精神病药物，包括促进血脂紊乱的奎硫平，作为有效的核激动剂 孕烷X受体(PXR)。我们之前的工作揭示了PXR在血脂中的新的和意想不到的作用 动态平衡和动脉粥样硬化，并表明PXR配体增加了血脂异常和动脉粥样硬化。 致动脉粥样硬化的小鼠模型，包括PXR人源化的小鼠。给定的肠道和淋巴系统 对于饮食中脂肪的吸收和运输至关重要，我们使用新的组织特异性PXR进行了最新的初步研究 基因敲除小鼠模型表明，暴露于奎硫平未能导致肠道高脂血症- 特定的PXR基因敲除小鼠。肠细胞中PXR信号如何调节肠脂代谢是一个 具有高度临床相关性的开放性问题。此外，我们的初步研究显示，消融PXR钝器 血管内皮生长因子受体3在淋巴管内皮细胞中的信号转导并减少淋巴管按键连接的形成 PXR缺陷小鼠的乳汁。淋巴PXR是如何调节脂质吸收的，目前尚不清楚。 通过肠道淋巴管运输。揭开上述中心谜团并研究其作用模式 PXR在介导抗精神病药物对血脂稳态和动脉粥样硬化的不良影响中的作用 提出以下具体目标以确定其致动脉粥样硬化作用的分子机制 非典型抗精神病药物：1)定义PXR激活抗精神病药物通过的肠细胞信号转导 调节血脂动态平衡和动脉粥样硬化；2)确定PXR的分子机制 动脉粥样硬化中受调节的淋巴脂吸收和转运；3)研究治疗 一种天然存在的PXR拮抗剂在预防抗精神病药物诱导的血脂异常和 动脉硬化。拟议工作的成功完成将填补发现新分子方面的空白 抗精神病药物治疗相关心血管疾病风险的潜在机制。我们的发现也可能开创新的 长期接受抗精神病药物治疗的患者血脂异常的治疗策略。

Project Summary Antipsychotic therapy is widely used in the treatment of psychiatric conditions including bipolar disorder, schizophrenia, and major depressive disorder. These conditions, which together affect more than 20% of the population, usually require lifelong medication. Atypical antipsychotics have superior therapeutic action and reduced adverse effects as compared with typical antipsychotics, but the use of atypical antipsychotics is also associated with dyslipidemia and an increased risk of cardiovascular disease (CVD) in patients. The underlying mechanisms responsible for these adverse effects remain largely unknown, which poses serious health challenges to patients undergoing long-term antipsychotic treatment. To this end, we recently identified several atypical antipsychotics including quetiapine that promote dyslipidemia, as potent agonists for the nuclear receptor pregnane X receptor (PXR). Our previous work revealed novel and unsuspected roles of PXR in lipid homeostasis and atherogenesis, and showed that PXR ligands increase dyslipidemia and atherosclerosis in atherogenic mouse models including PXR-humanized mice. Given intestine and lymphatic systems are essential for dietary lipid absorption and transport, our latest preliminary study using novel tissue-specific PXR knockout mouse models demonstrated that exposure to quetiapine fails to cause hyperlipidemia in intestine- specific PXR knockout mice. How PXR signaling in enterocytes regulates the intestinal lipid metabolism is an open and highly clinically relevant question. Furthermore, our pilot study revealed that ablation of PXR blunts VEGF receptor 3 signaling in lymphatic endothelial cells and reduces lymphatic button junction formation in lacteals of PXR-deficient mice. It is completely unknow how lymphatic PXR regulates lipid absorption and transport by gut lymphatic vessels. To unveil the aforementioned central mystery and to study the action mode of PXR in mediating antipsychotic-elicited adverse effects on lipid homeostasis and atherosclerosis, we propose the following specific aims to determine the molecular mechanisms of the atherogenic effects of atypical antipsychotics: 1) Define the enterocyte signaling through which PXR-activating antipsychotics regulate lipid homeostasis and atherosclerosis; 2) Determine the molecular mechanisms underlying PXR- regulated lymphatic lipid absorption and transport in atherosclerosis; and 3) Investigate the therapeutic potential of a naturally occurring PXR antagonist in preventing antipsychotic-induced dyslipidemia and atherosclerosis. Successful completion of the proposed work will fill in the void in uncovering novel molecular mechanisms underlying antipsychotic therapy-associated CVD risk. Our findings may also inaugurate new class of therapeutic strategies to treat dyslipidemia in patients undergoing long-term antipsychotic therapy.