Tissue-specific roles of FXR in CVD and NASH

项目摘要 项目2. FXR在CVD和NASH中的组织特异性作用 高血压和胰岛素抵抗通常与心血管和肝脏疾病有关， 然而，动脉粥样硬化和NASH之间的因果关系还没有很好地建立。法尼醇X 受体（FXR）是全身性固醇和葡萄糖稳态的调节剂，并且已知有助于 心血管和肝脏疾病的发生和发展。肝脏FXR丧失，但肠道FXR未丧失 FXR导致循环和肝脏胆固醇和甘油三酯水平升高。相比之下，肝脏和 肠FXR增强肝修复和胆固醇排泄活性。与此一致，FXR激动剂 可靠地减少动脉粥样硬化，并已报道在肝脏疾病模型中显示出有希望的效果。 因此，项目2的目标是在整合的背景下剖析FXR的组织特异性活动。 肝血管病理生理学具体来说，我们将探讨FXR驱动不同保护性 心血管和肝脏疾病的治疗方案。 巨噬细胞是通过沉积在动脉粥样硬化和脂肪性肝炎的发展中心 血管脂肪病变，以及驱动或解决肝损伤。作为炎症的关键调节因子， 在胆固醇逆向转运和排泄途径中，FXR是一个既定的靶点， 减轻了血管斑块沉积基础的泡沫细胞的形成。我们的初步研究结果 表明斑块沉积和肝脏疾病方面可通过FXR的组织特异性调节来划分 活动 本项目将探讨FXR的组织特异性调节将影响肿瘤进展的假设。 CVD和NASH。为了实现这一目标，靶向肝脏（hepFexD）或肠道的专有FXR激动剂 （intFexD）将与在肝脏（hepFXRko）中缺乏FXR表达的ldlr-/-小鼠组合使用，或与在肝脏（hepFXRko）中缺乏FXR表达的ldlr-/-小鼠组合使用。 肠道（intFXRko）来剖析脂肪肝疾病和CVD风险的关联。在目标1中， 将探讨肝FXR对动脉粥样硬化和肝病的作用，包括FXR- 与项目1合作，调节实质和非实质细胞之间的串扰， 肝脏FXR在OSE水平或清除中的作用，与项目3合作。在目标2中，系统的能力 来自肠道FXR的信号传导影响巨噬细胞胆固醇稳态将在合作中确定 项目1。最后，我们的临床前研究结果与人类疾病的相关性将通过以下方式确定： 与项目4合作，询问策划的临床样本中FXR活性的生物标志物。的 综合遗传学、药理学和比较生物学的方法将提供一个更好的 了解组织特异性FXR串扰影响的生理学和机制 动脉粥样硬化和脂肪性肝炎。

PROJECT SUMMARY Project 2. Tissue-specific roles of FXR in CVD and NASH Hyperlipidemia and insulin resistance are commonly associated with both cardiovascular and liver diseases, however causal relationships between atherosclerosis and NASH are not well established. The farnesoid X receptor (FXR) is a regulator of systemic sterol and glucose homeostasis, and is known to contribute to the initiation and progression of both cardiovascular and liver diseases. Loss of hepatic FXR, but not intestinal FXR, results in elevated circulating and hepatic cholesterol and triglyceride levels. In contrast, both hepatic and intestinal FXR enhance hepatic repair and cholesterol excretory activities. Consistent with this, FXR agonists reliably reduce atherosclerosis and have been reported to show promising effects in liver disease models. Thus, the goal of Project 2 is to dissect the tissue-specific activities of FXR in the context of integrative hepatovascular pathophysiology. Specifically, we will explore the notion that FXR drives distinct protective programs in cardiovascular and liver diseases. The macrophage is central in the development of atherosclerosis and steatotic hepatitis through the deposition of vascular fatty lesions, as well as driving or resolving liver damage. As a key regulator of inflammation and multiple steps in the reverse cholesterol transport and excretion pathways, FXR is an established target for mitigating the development of foam cells that underlie vascular plaque deposition. Our preliminary findings indicate that plaque deposition and facets of liver disease are divisible with tissue-specific modulation of FXR activities. This project will explore the hypothesis that tissue-specific modulation of FXR will affect the progression of CVD and NASH. To achieve this goal, proprietary FXR agonists that target either the liver (hepFexD) or gut (intFexD) will be used in combination with ldlr-/- mice lacking FXR expression in either the liver (hepFXRko) or the intestine (intFXRko) to dissect the association of fatty liver disease and CVD risk. In Aim 1, the impact of hepatic FXR on atherosclerosis and liver disease will be explored, including the contribution from FXR- regulated crosstalk between parenchymal and non-parenchymal cells in collaboration with Project 1, and the role for hepatic FXR in OSE levels or clearance in collaboration with Project 3. In Aim 2, the ability of systemic signaling from intestinal FXR to affect macrophage cholesterol homeostasis will be determined in collaboration with Project 1. Finally, the relevance of our pre-clinical findings studies to human disease will be determine by interrogating curated clinical samples for biomarkers of FXR activity in collaboration with Project 4. The proposed comprehensive genetic, pharmacologic and comparative biological approach will provide a better understanding of the physiology and mechanisms by which tissue-specific FXR crosstalk impacts atherosclerosis and steatohepatitis.