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: 10531887
• 负责人: Yi Tan
• 金额: $ 54.56万
• 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/10531887
• 关键词: Adipose tissue; Agonist; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Biliary; Binding Sites; Blood; Breeding; Cardiovascular Diseases; Cell Proliferation; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; 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; Life Style; Lipids; Liver; Macrophage; Mediating; Mediator; 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; clinical translation; db/db mouse; dietary; insight; 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，尤指血脂升高