A novel CREBH-derived hepatokine regulates triglyceride metabolism

一种新型 CREBH 衍生肝因子调节甘油三酯代谢

• 批准号: 10660331
• 负责人: Kezhong Zhang
• 金额: $ 43.3万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660331
• 关键词: ANGPTL3 gene; Animal Genetics; Animal Model; Atherosclerosis; Binding Proteins; Blood; Blood capillaries; C-terminal; Cardiovascular Diseases; Cells; Circulation; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Diet; Endoplasmic Reticulum; Endothelial Cells; Energy Metabolism; Exocytosis; Extracellular Space; Fasting; Fatty acid glycerol esters; Funding; Genetic Transcription; Golgi Apparatus; Hepatic; Homeostasis; Human; Hypertriglyceridemia; Intervention; Knockout Mice; Lipids; Lipolysis; Liver; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monitor; Mus; Names; Non-Insulin-Dependent Diabetes Mellitus; Organ; Overnutrition; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Plasma; Prevention; Process; Protein Fragment; Protein Secretion; Proteins; Proteolysis; Regulation; Regulatory Pathway; Risk Factors; Role; Stress; Stress-Induced Protein; Tertiary Protein Structure; Testing; Therapeutic Intervention; Tissues; Triglyceride Metabolism; Triglycerides; calmodulin-dependent protein kinase II; circadian regulation; flexibility; innovation; lipoprotein lipase; metabolic phenotype; non-alcoholic fatty liver disease; novel; prevent; reconstitution; response; sensor; therapy design; transcription factor; uptake

Project Summary: Hypertriglyceridemia, a condition in which blood triglyceride (TG) levels are elevated, is a major risk factor of metabolic and cardiovascular diseases, such as type-2 diabetes, atherosclerosis, and non- alcoholic fatty liver disease. Clearance of plasma TG is primarily mediated by lipoprotein lipase (LPL). LPL, expressed by the parenchymal cells of lipolytic tissues, is transported to capillary lumen by the endothelial cell transporter GPIHBP1, where it hydrolyzes plasma TG for local uptake into peripheral tissues. Although significant progress has been made, the fine-tune regulation of LPL activity as well as TG lipolysis and partitioning into peripheral tissues remain to be further elucidated. In the last funding cycle, we revealed that the endoplasmic reticulum (ER)-tethered, liver-enriched transcriptional factor CREBH functions as a diurnal metabolic regulator that integrates circadian regulation to energy homeostasis. Recently, we discovered that the C-terminal fragment of CREBH (CREBH-C), produced through Regulated Intramembrane Proteolysis (RIP), is secreted from the liver into circulation as a “hepatokine” upon energy demands. Secreted CREBH-C interacts with angiopoietin-like 3 (ANGPTL3) and ANGPTL8 to prevent the inhibitory interactions between ANGPTL3/8 and LPL, thus promoting LPL activity and TG partitioning into peripheral tissues. Circulatory CREBH-C promotes TG clearance and partitioning and mitigates hypertriglyceridemia caused by over-nutrition. These lines of evidence prompted us to hypothesize that ER membrane-tethered CREBH is processed by RIP to produce a novel hepatokine, CREBH-C, which interacts with ANGPTLs to regulate intravascular LPL activity, TG partitioning into peripheral tissues, and whole-body metabolism. CREBH-C intervention may increase metabolic flexibility and thus mitigate hypertriglyceridemia and the associated metabolic disorders. In this application, we will utilize molecular and cellular approaches, genetic animal models, as well as innovative LPL-monitoring and lipid-tracing approaches to define a novel hepatokine, CREBH-C, and its regulatory roles in LPL activity and TG homeostasis: Aim 1, to define the mechanistic pathway by which the ER membrane-tethered CREBH is processed to produce a secreted form of CREBH; Aim 2, to delineate the regulation and mechanistic basis by which CREBH-C interacts with ANGPTL3/8 to regulate LPL activity; Aim 3, to determine the functional significance of CREBH-C in regulating TG partitioning and whole- body metabolism and in mitigating hypertriglyceridemia and the associated metabolic phenotypes. Within the funding period, we anticipate defining a new paradigm that a stress-induced protein fragment, derived from the ER membrane protein CREBH, can function as a potent hepatokine to regulate lipid homeostasis and whole-body metabolism. Revealing this unprecedented regulatory pathway for CREBH and its derived hepatokine will have important implications in therapeutic interventions toward the control of hypertriglyceridemia and the associated metabolic and cardiovascular disorders.

项目摘要：高甘油三酯血症是一种血液甘油三酯 (TG) 水平升高的病症，是一种 代谢和心血管疾病的主要危险因素，如2型糖尿病、动脉粥样硬化和非 酒精性脂肪肝疾病的血浆 TG 清除主要由脂蛋白脂肪酶 (LPL) 介导。 由脂肪分解组织的实质细胞表达，由内皮细胞转运至毛细血管腔 转运蛋白 GPIHBP1，它水解血浆 TG 以局部摄取到外周组织中。 已取得进展，LPL 活性以及 TG 脂解和分配的微调调节 周围组织仍有待进一步阐明。 在上一个资助周期中，我们发现内质网（ER）束缚的、富含肝脏的 转录因子 CREBH 作为昼夜代谢调节剂，将昼夜节律调节整合到 最近，我们发现 CREBH (CREBH-C) 的 C 端片段产生。 通过调节膜内蛋白水解 (RIP)，作为“肝因子”从肝脏分泌到循环系统中 根据能量需求，分泌的 CREBH-C 与血管生成素样 3 (ANGPTL3) 和 ANGPTL8 相互作用 防止 ANGPTL3/8 和 LPL 之间的抑制性相互作用，从而促进 LPL 活性和 TG 分配 循环 CREBH-C 促进 TG 清除和分配并减轻 这些证据促使我们对营养过剩引起的高甘油三酯血症进行炒作。 膜束缚的 CREBH 通过 RIP 处理产生一种新型肝因子 CREBH-C，它与 ANGPTL 调节血管内 LPL 活性、TG 分配到外周组织和全身 CREBH-C 干预可能会增加代谢灵活性，从而减轻高甘油三酯血症和 在此应用中，我们将利用分子和细胞方法、遗传方法。 动物模型，以及创新的 LPL 监测和脂质追踪方法来定义新型肝因子， CREBH-C 及其在 LPL 活性和 TG 稳态中的调节作用：目标 1，定义机制途径 通过该方法，ER膜束缚的CREBH被加工以产生分泌形式的CREBH； 描述 CREBH-C 与 ANGPTL3/8 相互作用调节 LPL 的调节和机制基础 目标 3，确定 CREBH-C 在调节 TG 分配和整体中的功能意义 身体代谢并减轻高甘油三酯血症和相关的代谢表型。 在资助期内，我们预计定义一个新的范例，即压力诱导的蛋白质片段， 源自内质网膜蛋白 CREBH，可作为有效的肝因子调节脂质 揭示了 CREBH 及其前所未有的调节途径。 衍生的肝因子对于控制肝细胞因子的治疗干预具有重要意义 高甘油三酯血症以及相关的代谢和心血管疾病。