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有载脂蛋白B（apo B）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 中密度脂蛋白（IDL），然后是低密度脂蛋白（LDL）。当前胆固醇- 降低治疗主要通过增强LDL受体（LDLR）介导的LDL-胆固醇水平来靶向LDL-胆固醇水平 间隙然而，这些降低LDL的治疗（例如，他汀类药物和PCSK 9抑制剂）仅具有适度的 对残余的致动脉粥样硬化的含载脂蛋白B的脂蛋白胆固醇成分，包括VLDL-和 IDL-胆固醇。尽管通过这些降LDL治疗达到了LDL-胆固醇的最佳水平， 不受控制的VLDL-和IDL-胆固醇仍然显著促进高残余动脉粥样硬化 心血管疾病（CVD）的风险。我们的团队最近有了一个新的发现， 血凝块溶解蛋白，组织型纤溶酶原激活物（tPA），在肝细胞中限制apoB的产生。 小鼠和培养的原代肝细胞中的脂蛋白。本提案的总体目标是探讨 肝细胞tPA降低血浆含载脂蛋白B的脂蛋白胆固醇的潜在机制 程度.目的1：确定肝细胞tPA限制VLDL脂化的分子机制。分泌 极低密度脂蛋白颗粒的形成需要适当的载脂蛋白B脂化，但在我们对该机制的理解方面仍存在重大差距 发生这种情况的原因。我们的初步数据强烈支持我们的假设，沉默肝细胞tPA 通过促进肝脏VLDL脂化增加血浆apoB脂蛋白胆固醇。完成这一目标将 增加了新的见解，了解动脉粥样硬化apoB-脂蛋白的生产。目标2：确定 肝细胞tPA是否在分泌前增强apoB-VLDL的细胞内降解。细胞内 apoB-VLDL颗粒在其分泌之前的降解对于维持apoB-VLDL的最佳血浆水平是重要的。 致动脉粥样硬化的胆固醇和正常的肝脏脂质水平，但机制知之甚少。加大 在小鼠中肝细胞tPA表达以检验肝细胞tPA增强细胞内VLDL假设 分泌前降解。这一目标的完成将提供一种新的机制，以维持肝内 脂质稳态目的3：确定在血脂异常中增加肝细胞tPA是否会减少动脉粥样硬化， 而不会增加患脂肪肝的风险。降低循环残余胆固醇（在体内发现的胆固醇） VLDL和IDL），同时维持肝内脂质水平的稳态是一种有前途的策略， 残余动脉粥样硬化风险。然而，在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tPA表达在血脂异常小鼠中， 载脂蛋白B脂蛋白胆固醇，减少动脉粥样硬化，而不会在肝脏中积累脂质。完成 这一目标将提供新的治疗靶点以降低残余的动脉粥样硬化CVD风险。