The role of hepatocyte tPA in hepatic VLDL production.

肝细胞 tPA 在肝 VLDL 产生中的作用。

• 批准号: 10600838
• 负责人: Ze Zheng
• 金额: $ 51.99万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600838
• 关键词: Alteplase; Apolipoproteins B; Atherosclerosis; Binding; Blood; Blood coagulation; Cells; Cholesterol; Chronic; Cytolysis; Data; Diameter; Diet; Dyslipidemias; Fatty acid glycerol esters; Hepatic; Hepatocyte; Homeostasis; Human; Hypertriglyceridemia; IDL lipoproteins; Inflammatory Response; LDL Cholesterol Lipoproteins; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Molecular; Mus; Plasma; Plasminogen; Plasminogen Activator; Population; Production; Proteins; Residual state; Risk; Role; Serum; Source; Testing; Therapeutic; Triglycerides; Very low density lipoprotein; Very low density lipoprotein cholesterol; Wild Type Mouse; atherosclerosis risk; cardiovascular disorder risk; comparison control; fatty liver disease; inhibitor; insight; intrahepatic; lipoprotein cholesterol; new therapeutic target; novel; particle; therapeutic target

Atherosclerosis is initiated and promoted by the arterial accumulation of apolipoprotein B (apoB)-containing lipoproteins which activate a chronic inflammatory response. The hepatocyte is the major source of apoB- lipoprotein particles via its ability to secrete very-low-density lipoprotein (VLDL), which is then hydrolyzed into intermediate-density lipoprotein (IDL) and then low-density lipoprotein (LDL) in the blood. Current cholesterol- lowering therapies primarily target LDL-cholesterol levels by enhancing LDL receptor (LDLR)-mediated LDL clearance. However, these LDL-lowering treatments (e.g., statins and PCSK9 inhibitors) have only modest effects on the remnant atherogenic apoB-containing lipoprotein-cholesterol constituents, including VLDL- and IDL-cholesterol. Despite reaching optimal levels of LDL-cholesterol with these LDL-lowering treatments, uncontrolled VLDL- and IDL-cholesterols still significantly contribute to the high residual atherosclerotic cardiovascular disease (CVD) risk in the population. Our group recently made the novel discovery that a key blood clot lysis protein, tissue-type plasminogen activator (tPA), in hepatocytes limits the production of apoB- lipoproteins in mice and cultured primary hepatocytes. The overarching objective of this proposal is to explore the underlying mechanisms by which hepatocyte tPA lowers plasma apoB-containing lipoprotein-cholesterol levels. Aim 1: Determine the molecular mechanisms by which hepatocyte tPA limits VLDL lipidation. Secretion of VLDL particles requires proper apoB lipidation, but major gaps remain in our understanding of the mechanisms by which this happens. Our preliminary data strongly support our hypothesis that silencing hepatocyte tPA increases plasma apoB lipoprotein-cholesterol by promoting hepatic VLDL lipidation. Completion of this aim will add novel insights to the understanding of the production of atherogenic apoB-lipoproteins. Aim 2: Determine whether hepatocyte tPA enhances apoB-VLDL intracellular degradation before secretion. Intracellular degradation of apoB-VLDL particles prior to their secretion is important to maintain the optimal plasma levels of atherogenic cholesterol and normal liver lipid levels, but the mechanism is poorly understood. We will increase hepatocyte tPA expression in mice to test hypothesis that hepatocyte tPA enhances VLDL intracellular degradation before secretion. Completion of this aim will provide a novel mechanism to maintain intrahepatic lipid homeostasis. Aim 3: Determine whether increasing hepatocyte tPA in dyslipidemia reduces atherosclerosis, without raising the risk of fatty liver disease. Lowering circulating remnant cholesterol (the cholesterol found in VLDL and IDL) while maintaining the homeostasis of intrahepatic lipid levels is a promising strategy to reduce the residual atherosclerotic risk. However, therapeutic gaps remain in lowering atherogenic cholesterol without increasing liver lipid accumulation. We hypothesize that increasing tPA expression in dyslipidemic mice reduces apoB lipoprotein-cholesterol, alleviates atherosclerosis, without accumulating lipids in the liver. Completion of this aim will provide novel therapeutic targets to reduce residual atherosclerotic CVD risk.

动脉粥样硬化是由含载脂蛋白 B (apoB) 的动脉积聚引发和促进的 激活慢性炎症反应的脂蛋白。肝细胞是apoB的主要来源 脂蛋白颗粒通过其分泌极低密度脂蛋白（VLDL）的能力，然后被水解成 血液中的中密度脂蛋白（IDL）和低密度脂蛋白（LDL）。目前胆固醇- 降低 LDL 胆固醇水平的治疗主要通过增强 LDL 受体 (LDLR) 介导的 LDL 来实现 清除。然而，这些降低 LDL 的治疗（例如他汀类药物和 PCSK9 抑制剂）的作用有限。 对残余致动脉粥样硬化的含脂蛋白胆固醇成分的影响，包括 VLDL- 和 IDL-胆固醇。尽管通过这些降低 LDL 的治疗达到了 LDL 胆固醇的最佳水平， 不受控制的 VLDL 和 IDL 胆固醇仍然对高残留动脉粥样硬化有显着影响 人群中心血管疾病（CVD）的风险。我们的小组最近有了一个新的发现，那就是一个关键 肝细胞中的血凝块溶解蛋白、组织型纤溶酶原激活剂 (tPA) 限制了 apoB- 的产生 小鼠和培养的原代肝细胞中的脂蛋白。该提案的总体目标是探索 肝细胞 tPA 降低血浆 apoB 脂蛋白胆固醇的潜在机制 水平。目标 1：确定肝细胞 tPA 限制 VLDL 脂化的分子机制。分泌 VLDL 颗粒的合成需要适当的 apoB 脂化，但我们对其机制的理解仍存在重大差距 由此发生这种情况。我们的初步数据有力地支持了我们的假设：沉默肝细胞 tPA 通过促进肝脏 VLDL 脂化来增加血浆 apoB 脂蛋白胆固醇。这一目标的完成将 为理解致动脉粥样硬化 apoB 脂蛋白的产生增添了新的见解。目标 2：确定 肝细胞tPA是否增强apoB-VLDL在分泌前的细胞内降解。细胞内 apoB-VLDL 颗粒在分泌前的降解对于维持最佳血浆水平非常重要 致动脉粥样硬化的胆固醇和正常的肝脏脂质水平有关，但其机制尚不清楚。我们将增加 小鼠肝细胞 tPA 表达，检验肝细胞 tPA 增强细胞内 VLDL 的假设 分泌前降解。这一目标的完成将为维持肝内功能提供一种新的机制。 脂质稳态。目标 3：确定血脂异常时增加肝细胞 tPA 是否会减少动脉粥样硬化， 不会增加患脂肪肝的风险。降低循环残余胆固醇（存在于 VLDL 和 IDL）同时维持肝内脂质水平的稳态是减少 残余动脉粥样硬化风险。然而，在不降低致动脉粥样硬化胆固醇方面仍存在治疗差距。 增加肝脏脂质积累。我们假设增加血脂异常小鼠中的 tPA 表达会降低 apoB 脂蛋白胆固醇，可减轻动脉粥样硬化，且不会在肝脏中积聚脂质。完成 这一目标将为降低残余动脉粥样硬化 CVD 风险提供新的治疗靶点。