Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis

成纤维细胞生长因子 1 预防高脂血症和动脉粥样硬化

基本信息

批准号：
10345440
负责人：
Yi Tan
金额：
$ 55.36万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10345440
关键词：
Adipose tissue Agonist Animal Model Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Attenuated Biliary Binding Sites Blood Cardiovascular Diseases Cell Proliferation Cells Cholesterol Cholesterol Homeostasis Chronic Clinical Clinical Research Coagulation Process Data Development Diabetes Mellitus Dose Dyslipidemias Engineering Enterocytes FGF1 gene Feces Fluorescein Future Genetic Transcription Heparin Binding Hepatic Hepatocyte Human Hyperlipidemia Intestinal Absorption Intestines Knockout Mice LDL Cholesterol Lipoproteins Label Lead Life Style Lipids Liver Mediating Mediator of activation protein Metabolic Metabolic syndrome Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Translocation Operative Surgical Procedures Organ Organoids Pathogenesis Pathologic Patients Phenotype Play Prevention approach Radioisotopes Recombinants Regulation Risk Risk Factors Role Site Testing Therapeutic Up-Regulation Variant angiogenesis atherogenesis blood glucose regulation cholesterol absorption cholesterol biosynthesis clinical practice db/db mouse dietary insight macrophage neovascularization non-alcoholic fatty liver disease novel novel strategies novel therapeutic intervention overexpression prevent side effect transcription factor translational potential tumorigenic

项目摘要

Atherosclerosis is a narrowing of arteries caused by plaque buildup. Dyslipidemia, especially elevated low- density lipoprotein cholesterol, is a major risk factor for atherosclerotic plaque formation. Current therapies for atherosclerosis focus on lowering cholesterol. However, conventional lipid lowering therapies (such as statins) are associated with obvious side effects. Developing more specific and efficient treatments are needed. Fibroblast growth factor 1 (FGF1) has been widely studied for its therapeutic benefits in cardiovascular disorders primary utilization of its mitogenic functions. Recently, FGF1 was shown to exert an unexpected metabolic activity by regulating adipose remodeling and glucose homeostasis, demonstrating a potential for treatment of metabolic syndrome. However, wild-type FGF1 (FGF1WT) induced hyperproliferation can lead to increased tumorigenic risk; this becomes the primary obstacle for its widespread application. To reduce this risk, we recently engineered a partial FGF1 agonist carrying triple mutations of the heparin-binding sites (FGF1ΔHBS), which abolished proliferative potential, but maintains full FGF1WT metabolic activity. Notably, chronic treatment of db/db mice with FGF1ΔHBS almost completely reversed diabetes-associated NAFLD. These findings suggest that FGF1ΔHBS is a potentially safe and efficient therapeutic approach for treatment of metabolic syndrome. Although characterization of the metabolic functions of FGF1 is ongoing, little is known about its roles in atherosclerosis. A small case observation found an increased FGF1 expression in neovascularized and macrophage-rich regions of plaque, implying a potential pathological role of FGF1 in human atherogenesis. However, whether and how FGF1 plays beneficial or detrimental roles in atherogenesis remain unexplored. We recently examined the impact of FGF1 administration on the pathogenesis of atherosclerosis in ApoE-KO mice and found that FGF1ΔHBS markedly ameliorated atherosclerotic phenotypes without significant proliferative potential in liver. Furthermore, FGF1 treatment reduced cholesterol levels in the blood, liver and intestine, but increased cholesterol contents in feces. These preliminary data indicate that FGF1 regulation of cholesterol homeostasis in both liver and intestine is responsible for its protection from atherosclerosis. The liver is a major site for cholesterol biosynthesis while the intestine maintains cholesterol homeostasis by mediating intestinal absorption of dietary and biliary cholesterol. Therefore, we hypothesize that non-mitogenic variant FGF1ΔHBS prevents atherosclerosis by inhibiting hepatic cholesterol synthesis and suppressing intestinal cholesterol absorption without risks of hyperproliferation. We will test the hypothesis in three specific aims: 1) Determine the roles of FGF1 in the development of atherosclerosis; 2) Determine the effects and mechanism of FGF1 on hepatic cholesterol biosynthesis; 3) Determine the effects and mechanism of FGF1 on intestinal cholesterol absorption. This project will provide fundamental evidence for FGF1ΔHBS acting at the hepatocytes and intestinal enterocytes as a novel approach for the prevention of atherosclerosis in future clinical studies.

动脉粥样硬化是由斑块堆积引起的动脉狭窄，尤其是血脂异常升高。密度脂蛋白胆固醇是目前治疗动脉粥样硬化斑块的主要危险因素。动脉粥样硬化的重点是降低胆固醇，但传统的降脂疗法（如他汀类药物）。需要开发更具体和有效的治疗方法。成纤维细胞生长因子 1 (FGF1) 因其对心血管疾病的治疗作用而得到广泛研究最近，FGF1 被证明具有意想不到的代谢活性。通过调节脂肪重塑和葡萄糖稳态，展示了治疗代谢性疾病的潜力然而，野生型 FGF1 (FGF1WT) 诱导的过度增殖可能导致致瘤风险增加；这成为其广泛应用的主要障碍，为了降低这种风险，我们最近设计了一个。部分 FGF1 激动剂携带肝素结合位点的三重突变 (FGF1ΔHBS)，从而废除了增殖潜力，但保持完整的 FGF1WT 代谢活性值得注意的是，对 db/db 小鼠进行长期治疗。 FGF1ΔHBS 几乎完全逆转了糖尿病相关的 NAFLD。这些发现表明 FGF1ΔHBS 是一种治疗代谢综合征的潜在安全有效的治疗方法。尽管 FGF1 代谢功能的表征正在进行中，但对其在代谢中的作用知之甚少。一项小病例观察发现新生血管和动脉粥样硬化中 FGF1 表达增加。斑块中富含巨噬细胞的区域，这意味着 FGF1 在人类动脉粥样硬化形成中具有潜在的病理作用。然而，FGF1 在动脉粥样硬化形成中是否以及如何发挥有益或有害作用仍有待探索。最近研究了 FGF1 给药对 ApoE-KO 小鼠动脉粥样硬化发病机制的影响并发现 FGF1ΔHBS 显着改善动脉粥样硬化表型，而没有显着的增殖作用此外，FGF1 治疗降低了血液、肝脏和肠道中的胆固醇水平，但这些初步数据表明 FGF1 对胆固醇的调节作用。肝脏和肠道的稳态是防止动脉粥样硬化的主要因素。胆固醇生物合成的场所，而肠道通过介导肠道维持胆固醇稳态因此，我们寻找非促有丝分裂变体 FGF1ΔHBS。通过抑制肝脏胆固醇合成和抑制肠道胆固醇来预防动脉粥样硬化胆固醇吸收没有过度增殖的风险，我们将在三个具体目标上检验这一假设： 1) 确定FGF1在动脉粥样硬化发展中的作用 2) 确定作用和机制； FGF1对肝脏胆固醇生物合成的影响；3)确定FGF1对肠道的影响和机制；该项目将为FGF1ΔHBS作用于肝细胞提供基本证据。和肠肠细胞作为未来临床研究中预防动脉粥样硬化的新方法。