Tissue-specific roles of FXR in CVD and NASH

FXR 在 CVD 和 NASH 中的组织特异性作用

• 批准号: 10262919
• 负责人: RONALD M EVANS
• 金额: $ 42.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262919
• 关键词: Affect; Agonist; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Bile Acids; Biliary; Biological; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Ulcerating Plaque; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Collaborations; Coronary Arteriosclerosis; Deposition; Development; Dietary Component; Disease; Disease model; Epitopes; Excretory function; Extrahepatic; FGF19 gene; Fatty Liver; Fibrosis; Foam Cells; Functional disorder; Gap Junctions; Genetic; Genetic Transcription; Goals; Hepatic; Hepatitis; High Density Lipoproteins; Hyperlipidemia; In Vitro; Inflammation; Insulin Resistance; Intestines; Lesion; Lipids; Lipoproteins; Liver; Liver diseases; Lysophosphatidylcholines; Mediating; Metabolism; Modeling; Mus; Pathway interactions; Patients; Peptides; Pharmacology; Physiology; Predictive Value; Receptor Activation; Regulation; Reporting; Risk; Role; Sampling; Serum; Signal Transduction; Steatohepatitis; Tissues; Triglycerides; atherogenesis; biobank; blood glucose regulation; cardiovascular disorder risk; comparative; disorder risk; gain of function; human disease; indexing; insight; liver injury; loss of function; macrophage; mouse model; nonalcoholic steatohepatitis; oxidation; patient population; pre-clinical; programs; protective effect; receptor; receptor expression; repaired; repository; reverse cholesterol transport; sterol homeostasis; targeted treatment

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.

项目摘要 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疾病和肝病都相关， 但是，动脉粥样硬化与纳什之间的因果关系并不确定。 Farnesoid X 受体（FXR）是全身固醇和葡萄糖稳态的调节剂，已知有助于 心血管疾病和肝病的起始和进展。肝FXR的丧失，但不是肠道 FXR，导致循环和肝胆固醇和甘油三酸酯水平升高。相反，肝和 肠道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，并据报道在肝病模型中显示出令人鼓舞的影响。 因此，项目2的目标是在综合的背景下剖析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驱动独特保护性的观念 心血管疾病和肝病的程序。 巨噬细胞在通过沉积中开发动脉粥样硬化和脂肪变性肝炎是核心 血管脂肪病变，以及驾驶或解决肝脏损伤。作为炎症和 反向胆固醇运输和排泄途径的多个步骤，FXR是既定目标 减轻血管斑块沉积基础的泡沫细胞的发育。我们的初步发现 表明牙菌性沉积和肝病的面可与FXR的组织特异性调节分开 活动。 该项目将探讨以下假设：FXR的组织特异性调制将影响 CVD和NASH。为了实现这一目标，针对肝脏（HEPFEXD）或肠道的专有FXR激动剂 （intfexd）将与肝脏（hepfxrko）中缺乏FXR表达的LDLR - / - 小鼠联合使用（HEPFXRKO）或 肠道（INTFXRKO）剖析脂肪肝病与CVD风险的关联。在AIM 1中， 将探讨有关动脉粥样硬化和肝病的肝FXR，包括FXR-的贡献 在与项目1合作的实质和非副质细胞之间的调节串扰 肝FXR在OSE级别或与项目3合作的级别中的作用。在AIM 2中，系统性的能力 将在合作中确定肠道FXR的信号传导影响巨噬细胞胆固醇稳态 最后，我们的临床前研究结果与人类疾病的相关性将由 与项目4合作，询问精选的FXR活性生物标志物的临床样品。 拟议的综合遗传，药理学和比较生物学方法将提供更好的 了解组织特异性FXR串扰影响的生理和机制 动脉粥样硬化和脂肪性肝炎。