Hepatic Rap1a in cholesterol homeostasis

肝脏 Rap1a 在胆固醇稳态中的作用

• 批准号: 10736498
• 负责人: Lale Ozcan
• 金额: $ 64.58万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736498
• 关键词: Acute; Antibodies; Arterial Fatty Streak; Atherosclerosis; Attenuated; Back; Binding; Biochemical; CETP gene; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cholesterol; Cholesterol Homeostasis; Clinic; Data; Development; Diabetic mouse; Dose; Drug Prescriptions; Epidemic; Etiology; Event; Glucagon Receptor; Glucose Intolerance; Goals; Healthcare Systems; Hepatic; Hepatocyte; Human; Hyperlipidemia; Insulin Resistance; Knockout Mice; LDL Cholesterol Lipoproteins; Laboratories; Lesion; Link; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Messenger RNA; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Physiology; Plasma; Post-Transcriptional Regulation; Prevention; Proprotein Convertase 1; Proprotein Convertases; Proteins; Proteomics; RAS Superfamily Proteins; Regulation; Reporting; Residual state; Role; Serum; Societies; Specificity; Subtilisins; Testing; Therapeutic; Work; apolipoprotein E-3; blood glucose regulation; cardiovascular disorder risk; cardiovascular disorder therapy; gain of function; geranylgeranyl pyrophosphate; geranylgeranylation; glucose production; improved; in vivo; inhibitor; insight; isoprenoid; mouse genetics; mouse model; mutant; new therapeutic target; novel; pharmacologic; pleiotropism; prenylation; preservation; prevent; restoration; small molecule; targeted treatment; therapeutic target

PROJECT SUMMARY Title: Hepatic Rap1a in cholesterol homeostasis Atherosclerotic cardiovascular disease is the leading cause of death worldwide and lowering of proatherogenic low-density lipoprotein (LDL) cholesterol (LDL-C) levels is the primary target of therapy. Recent work has identified proprotein convertase subtilisin/ kexin type 9 (PCSK9) as a promising therapeutic target that regulates serum LDL-C. Despite its critical role as a regulator of the LDL receptor (LDLR) and attractiveness as a pharmacological target, the mechanism(s) by which PCSK9 is regulated remain largely unknown. Interestingly, the most widely prescribed drugs for lowering plasma cholesterol, statins, dose-dependently increase PCSK9 levels, which largely negate further statin-induced increases in hepatic LDLR and attenuate their efficacy. However, our understanding of the underlying cellular and molecular mechanisms of this regulation remains incomplete. This proposal is based on a new finding from our laboratory suggesting that activation of the small G protein of the Ras superfamily, Rap1a, lowers PCSK9 and plasma LDL-C levels. Further, Rap1a geranylgeranyl prenylation and activity is inhibited in statin-treated hepatocytes and human liver, and restoring intracellular geranylgeranyl isoprenoid levels prevents statin-induced PCSK9 and further lowers LDL-C. We propose that hepatic Rap1a is a novel regulator of PCSK9 protein, and its inhibition via lower intracellular isoprenoid levels may provide an additional mechanism to explain how statins increase PCSK9. Based on these, we will define the mechanisms by which Rap1a regulates PCSK9 and LDL-C metabolism (Aim 1), elucidate it’s in role statin-mediated PCSK9 induction (Aim 2), and explore the effect of combined statin and Rap1a activation in the prevention of atherosclerotic lesion development. (Aim 3). We will test these new ideas in vivo and ex vivo, using a combination of mouse genetic, physiological, and biochemical approaches.

项目概要 标题：肝脏 Rap1a 在胆固醇稳态中的作用 动脉粥样硬化性心血管疾病是全世界死亡的主要原因，并且降低了促动脉粥样硬化的发生率。 低密度脂蛋白（LDL）胆固醇（LDL-C）水平是治疗的主要目标。最近的工作有 确定前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 是一个有前途的治疗靶点，可调节 血清低密度脂蛋白胆固醇。尽管它作为 LDL 受体 (LDLR) 的调节剂发挥着重要作用，并且作为一种药物具有吸引力 作为药理学靶点，PCSK9 的调节机制仍然很大程度上未知。有趣的是， 最广泛使用的降低血浆胆固醇药物——他汀类药物，可剂量依赖性地增加 PCSK9 水平，这在很大程度上抵消了他汀类药物引起的肝脏 LDLR 的进一步增加并削弱了其功效。 然而，我们对这种调节的潜在细胞和分子机制的理解仍然存在 不完整。该提议基于我们实验室的一项新发现，表明小分子的激活 Ras 超家族的 G 蛋白 Rap1a 可降低 PCSK9 和血浆 LDL-C 水平。此外，Rap1a 在他汀类药物处理的肝细胞和人肝脏中，香叶基香叶基异戊二烯化和活性受到抑制，并恢复 细胞内香叶基香叶基异戊二烯水平可防止他汀类药物诱导的 PCSK9 并进一步降低 LDL-C。我们 提出肝 Rap1a 是 PCSK9 蛋白的新型调节因子，其抑制作用通过降低细胞内 类异戊二烯水平可能提供额外的机制来解释他汀类药物如何增加 PCSK9。基于这些， 我们将定义 Rap1a 调节 PCSK9 和 LDL-C 代谢的机制（目标 1），阐明其作用 在他汀类药物介导的 PCSK9 诱导中发挥作用（目标 2），并探索他汀类药物和 Rap1a 联合激活的效果 预防动脉粥样硬化病变的发展。 （目标 3）。我们将在体内和体外测试这些新想法， 结合小鼠遗传、生理和生化方法。