Tissue-specific roles of FXR in CVD and NASH

项目总结 项目2.FXR在CVD和NASH中的组织特异性作用 高脂血症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之间的因果关系尚未得到很好的证实。法尼斯类X 受体(FXR)是全身类固醇和葡萄糖稳态的调节器，并被认为有助于 心血管和肝脏疾病的发生和发展。肝脏FXR的丢失，但不是肠道 FXR会导致循环和肝脏胆固醇和甘油三酯水平升高。相比之下，肝脏和肝脏 肠道FXR增强肝脏修复和胆固醇排泄活动。与此一致，FXR激动剂 可靠地减少动脉粥样硬化，并已被报道在肝脏疾病模型中显示出良好的效果。 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。具体地说，我们将探索FXR驱动独特的保护 心血管和肝脏疾病方面的计划。 巨噬细胞通过沉积在动脉粥样硬化和脂肪性肝炎的发展中起中心作用。 血管脂肪损伤，以及驱动或解决肝脏损伤。作为炎症和炎症的关键调节因子 在反向胆固醇运输和排泄途径的多个步骤中，FXR是一个既定的靶点 减缓泡沫细胞的发展，泡沫细胞是血管斑块沉积的基础。我们的初步调查结果 提示肝脏疾病的斑块沉积和小关节可与FXR的组织特异性调节相区分 活动。 该项目将探索组织特异性调节FXR将影响血管紧张素转换酶进展的假说。 心血管疾病和纳什。为了实现这一目标，针对肝脏(HepFexD)或肠道的专利FXR激动剂 (IntFexD)将与肝脏FXR表达缺失的LDLR-/-小鼠(HepFXRko)或 肠道(IntFXRko)来剖析脂肪肝和心血管疾病风险之间的联系。在目标1中， 将探讨肝脏FXR对动脉粥样硬化和肝病的作用，包括FXR- 与项目1合作，在实质细胞和非实质细胞之间调节串扰，以及 与项目3合作，肝脏FXR在OSE水平或清除中的作用。在目标2中，系统性 肠道FXR影响巨噬细胞胆固醇稳态的信号将在合作中确定 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，询问精选的临床样本以寻找FXR活性的生物标记物。 拟议的遗传学、药理学和比较生物学综合方法将提供更好的 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.