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

• 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
• 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

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。血脂异常，尤指升高的低脂 密度脂蛋白胆固醇是动脉粥样硬化斑块形成的主要危险因素。目前的治疗方法 动脉粥样硬化的重点是降低胆固醇。然而，传统的降脂疗法(如他汀类药物) 都与明显的副作用有关。需要开发更具体、更有效的治疗方法。 成纤维细胞生长因子1(FGF1)因其在心血管疾病中的治疗作用而被广泛研究 其促有丝分裂功能的初步利用。最近，FGF1被证明具有一种意想不到的代谢活性 通过调节脂肪重塑和葡萄糖稳态，展示了治疗代谢疾病的潜力 综合症。然而，野生型FGF1(FGF1WT)诱导的过度增殖可导致肿瘤发生风险增加； 这成为其广泛应用的主要障碍。为了降低这种风险，我们最近设计了一种 携带肝素结合位点三倍突变的部分FGF1激动剂(FGF1ΔHBs)，它取消了 增殖潜力，但保持完整的FGF1WT代谢活性。值得注意的是，慢性用药治疗db/db小鼠 FGF1ΔHBS几乎完全逆转了糖尿病相关的非酒精性脂肪肝。这些发现表明，FGF1ΔHBs是一种 潜在安全有效的代谢综合征治疗方法。 尽管对FGF1的代谢功能的描述仍在进行中，但对其在 动脉硬化。一个小病例观察发现，FGF1在新生血管和 斑块中巨噬细胞丰富的区域，暗示FGF1在人类动脉粥样硬化形成中的潜在病理作用。 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不清楚。我们 最近研究了FGF1对载脂蛋白E-KO小鼠动脉粥样硬化发病机制的影响 并发现FGF1、Δ、HBs可显著改善动脉粥样硬化表型，但无明显增殖性 肝脏中的潜在性。此外，FGF1治疗降低了血液、肝脏和肠道中的胆固醇水平，但 增加粪便中的胆固醇含量。这些初步数据表明，FGF1对胆固醇的调节 肝脏和肠道的动态平衡是其免受动脉粥样硬化影响的原因。肝脏是一种主要的 胆固醇生物合成的场所，而肠道通过调节肠道来维持胆固醇的动态平衡 饮食和胆汁胆固醇的吸收。因此，我们假设非有丝分裂变异体FgF1ΔHBs 通过抑制肝脏胆固醇合成和抑制肠道来预防动脉粥样硬化 吸收胆固醇，不存在过度增殖的风险。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)确定其作用和机制 FGF1对肝脏胆固醇生物合成的影响；3)确定FGF1对肠道的影响及其机制 胆固醇的吸收。本项目将为FGF1ΔHBs作用于肝细胞提供基础证据。 肠上皮细胞作为预防动脉粥样硬化的新途径将在未来的临床研究中发挥作用。