FAK regulation of cholesterol influx and efflux in foam cells

FAK 对泡沫细胞中胆固醇流入和流出的调节

• 批准号: 10278516
• 负责人: Steve Lim
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278516
• 关键词: ATP binding cassette transporter 1; Actins; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; CD36 gene; CSF1R gene; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Cholesterol Homeostasis; Complex; Data; Endocytosis; Equilibrium; Excision; Foam Cells; Focal Adhesion Kinase 1; Gene Expression; Genetic; Genetic Transcription; Homeostasis; Inflammation; Integrins; Ischemic Stroke; LXRalpha protein; Lipids; Mediating; Modeling; Molecular; Mus; Myocardial Infarction; NCOR2 gene; Nuclear; Nuclear Protein; Nuclear Receptors; Nuclear Translocation; PPAR alpha; PPAR gamma; Patients; Pharmacology; Phosphotransferases; Population; Preventive; Protein Tyrosine Kinase; Regulation; Role; Signal Transduction; Therapeutic; antiporter; cell motility; filamin; genetic corepressor; insight; macrophage; mortality; mouse model; oxidized low density lipoprotein; patient subsets; prevent; scavenger receptor; sensor; targeted treatment; uptake; western diet

Project Summary Atherosclerosis arises as a result of excess accumulation of cholesterol within vascular cells, with macrophages comprising a majority of these lipid-laden foam cells within atherosclerotic lesions. Lipid-lowering therapies, such as statins, have proven beneficial, but still only benefit a subset of patients. As such, there is currently a need to develop new treatment options that can treat a larger portion of atherosclerosis patients to reduce cardiovascular disease mortality. One potential strategy for treating atherosclerosis is to reduce foam cells by decreasing cholesterol uptake (influx) and/or to promote cholesterol release (efflux) in macrophages. However, no current therapy targets these mechanisms. Foam cells within atherosclerotic lesions are developed from too much cholesterol influx without efficient efflux. Focal adhesion kinase (FAK) is an integrin- associated tyrosine kinase which contributes to vascular cell migration, proliferation, and inflammation. We have discovered new functions for FAK in the regulation of lipid homeostasis within macrophages. Our preliminary data revealed that FAK activation following oxidized low-density lipoprotein (oxLDL) stimulation was required for foam cell formation via endocytosis of CD36. Additionally, oxLDL increased FAK interaction with CD36 and Filamin A. Importantly, pharmacological FAK inhibition blocked FAK-CD36-Filamin A interaction and subsequent foam cell formation, suggesting that the ternary complex may contribute to oxLDL uptake. More interestingly, FAK inhibition increased expression of cellular lipid sensors peroxisome proliferator activated receptor g (PPARg) and liver X receptor a (LXRa) resulting in increased transcription of the cholesterol antiporters ABCG1 and ABCA1. FAK inhibition also increased PPARg and LXRa nuclear translocation, and this was associated with decreased expression of nuclear receptor corepressor 2 (NCOR2). In a new macrophage-specific FAK kinase-dead (KD) mouse model (CSF1R-iCre) on ApoE-/- background, we observed that FAK-KD mice fed a western diet (WD) showed less foam cell formation and reduced atherosclerotic lesions. Taken together, our central hypothesis is that FAK inhibition reduces oxLDL uptake via disruption of FAK-Filamin A-CD36 complex formation while also increasing cholesterol efflux through increased PPARg and LXRa activation via NCOR2 degradation. To decipher a molecular mechanism in which a two-fold role of FAK prevents cholesterol uptake as well as enhances efflux in macrophages. Aim 1 will determine FAK and Filamin A regulation of oxLDL-CD36 uptake in macrophages. Aim 2 will investigate FAK regulation of cholesterol efflux via PPARg and LXRa activation in foam cells. Aim 3 will evaluate the effect of FAK inhibition on preventive and therapeutic models of atherosclerosis. The proposed study will shed new insights on the role of FAK in cholesterol homeostasis in macrophage foam cells and could produce a new treatment option in atherosclerosis by reducing the foam cells via reduced cholesterol influx and elevated cholesterol efflux.

项目总结