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.

动脉粥样硬化是斑块堆积引起的动脉的狭窄。血脂异常，尤其是低升高 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。当前的疗法 动脉粥样硬化的重点是降低胆固醇。但是，常规的脂质降低疗法（例如他汀类药物） 与明显的副作用有关。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）已广泛研究其在心血管疾病中的治疗益处 主要利用其有丝分裂功能。最近，FGF1被证明执行了意外的代谢活动 通过调节脂肪重塑和葡萄糖稳态，证明了代谢治疗的潜力 综合征。但是，野生型FGF1（FGF1WT）诱导的过度增殖会导致肿瘤风险增加。 这成为其宽度应用程序的主要障碍。为了降低这种风险，我们最近设计了 部分FGF1激动剂携带肝素结合位点的三重突变（FGF1ΔHB），该突变被废除 增殖潜力，但保持全面的FGF1WT代谢活性。值得注意的是，与DB/DB小鼠的慢性治疗 FGF1ΔHB几乎完全逆转了与糖尿病相关的NAFLD。这些发现表明FGF1ΔHB是一个 代谢综合征治疗的潜在安全有效的热方法。 尽管FGF1代谢功能的表征仍在进行中，但对其在其在 动脉粥样硬化。一个小病例观察发现，在新血管中的FGF1表达增加和 斑块富含巨噬细胞的区域，这意味着FGF1在人动脉粥样硬化中的潜在病理作用。 但是，FGF1在动脉粥样硬化中发挥有益或有害作用是出乎意料的。我们 最近检查了FGF1给药对APOE-KO小鼠动脉粥样硬化发病机理的影响 并发现FGF1ΔHB明显改善动脉粥样硬化表型而没有显着增殖 潜力在肝脏中。此外，FGF1治疗降低了血液，肝脏和肠道的胆固醇水平，但 粪便中胆固醇含量增加。这些初步数据表明FGF1调节胆固醇 肝脏和肠道中的稳态均负责保护其免受动脉粥样硬化的保护。肝脏是主要的 胆固醇生物合成的位点，而肠道通过介导肠道胆固醇稳态维持胆固醇 饮食和胆汁胆固醇的吸收。因此，我们假设非触发变体FGF1ΔHBS 通过抑制肝胆固醇的合成和抑制肠道来防止动脉粥样硬化 胆固醇遭受痛苦，没有过度增殖的风险。我们将以三个具体目的测试该假设： 1）确定FGF1在动脉粥样硬化发展中的作用； 2）确定效果和机制 肝胆固醇生物合成上的FGF1； 3）确定FGF1对肠道的影响和机制 胆固醇滥用。该项目将为作用于肝细胞的FGF1ΔHB提供基本证据 在未来的临床研究中，肠肠上皮细胞是预防动脉粥样硬化的一种新方法。