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.

项目总结