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: 10420269
• 负责人: Ze Zheng
• 金额: $ 52.14万
• 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/10420269
• 关键词: Alteplase; Apolipoproteins B; Atherosclerosis; Binding; Blood; Blood coagulation; Caliber; Cells; Cholesterol; Chronic; Cytolysis; Data; 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; base; cardiovascular disorder risk; 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.

动脉粥样硬化是通过载脂蛋白B（APOB）的动脉积累来启动和促进的 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非常低密度脂蛋白（VLDL）的能力，然后将其水解为 血液中的中等密度脂蛋白（IDL），然后在血液中低密度脂蛋白（LDL）。当前胆固醇 - 通过增强LDL受体（LDLR）介导的LDL降低疗法主要靶向LDL-胆固醇水平 清除。但是，这些降低LDL的疗法（例如他汀类药物和PCSK9抑制剂）只有适中 对含含APOB的脂蛋白 - 胆固醇成分的残余动脉粥样硬化性的影响，包括VLDL-和 IDL-胆固醇。尽管使用这些降低LDL的疗法达到了最佳水平的LDL-胆固醇，但 不受控制的VLDL-和IDL-胆固醇仍然显着有助于高残余动脉粥样硬化 人口中的心血管疾病（CVD）风险。我们的小组最近将小说发现是关键 血凝块裂解蛋白，组织型纤溶酶原激活剂（TPA），在肝细胞中限制了ApoB-的产生 小鼠和培养的原发性肝细胞中的脂蛋白。该提议的总体目标是探索 肝细胞TPA降低血浆APOB的脂蛋白 - 胆固醇的基本机制 水平。目标1：确定肝细胞TPA限制VLDL脂质的分子机制。分泌 VLDL颗粒的含量需要适当的APOB脂化，但是我们对机制的理解仍然存在主要差距 发生这种情况。我们的初步数据强烈支持我们的假设，即沉默的肝细胞TPA 通过促进肝VLDL脂质化来增加血浆APOB脂蛋白 - 胆固醇。这个目标的完成 在理解动脉粥样硬化APOB-脂蛋白的产生时增加新的见解。目标2：确定 肝细胞TPA是否会在分泌前增强APOB-VLDL细胞内降解。细胞内 APOB-VLDL颗粒在分泌之前的降解对于保持最佳血浆水平很重要 动脉粥样硬化胆固醇和正常的肝脂质水平，但该机制知之甚少。我们将增加 小鼠中的肝细胞TPA表达，以测试肝细胞TPA增强VLDL细胞内的假设 分泌前退化。该目标的完成将提供一种新型的机制来维持肝脏内部 脂质稳态。 AIM 3：确定血脂异常增加肝细胞TPA是否会降低动脉粥样硬化， 不增加脂肪肝病的风险。降低循环残留胆固醇（胆固醇 VLDL和IDL）在保持肝内脂质水平的体内稳态时是一种有希望的策略 残留的动脉粥样硬化风险。但是，治疗差距仍在降低动脉粥样硬化胆固醇中 增加肝脂质积累。我们假设增加血脂性小鼠中TPA表达会减少 APOB脂蛋白 - 胆固醇减轻了动脉粥样硬化，而无需在肝脏中积聚脂质。完成 该目标将提供新的治疗靶标，以降低残留的动脉粥样硬化CVD风险。