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）水平升高的疾病，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 酒精性脂肪肝血浆TG的清除主要由脂蛋白脂酶（LPL）介导。LPL， 由脂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GPIHBP 1，在此其水解血浆TG以局部摄取到外周组织中。虽然显著 已经取得了进展，LPL活性的微调调节以及TG脂解和分配到 外周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，肝脏富集， 转录因子CREBH作为昼夜代谢调节因子发挥作用， 能量平衡最近，我们发现CREBH的C-末端片段（CREBH-C）， 通过调节性膜内蛋白水解（RIP），作为“肝细胞因子”从肝脏分泌到循环中。 能源需求。分泌型CREBH-C与血管生成素样3（ANGPTL 3）和ANGPTL 8相互作用， 阻止ANGPTL 3/8和LPL之间的抑制性相互作用，从而促进LPL活性和TG分配 进入外周组织循环CREBH-C促进TG清除和分配， 营养过剩引起的高血糖症。这些证据促使我们假设ER 膜系CREBH被RIP加工产生一种新的肝细胞因子CREBH-C，它与 ANGPTLs调节血管内LPL活性，TG分配到外周组织和全身 新陈代谢. CREBH-C干预可增加代谢灵活性，从而减轻高脂血症， 相关的代谢紊乱在本申请中，我们将利用分子和细胞方法，遗传学方法， 动物模型，以及创新的LPL监测和脂质追踪方法来定义一种新的肝细胞因子， CREBH-C及其在LPL活性和TG稳态中的调节作用：目的1，确定机制途径 通过该方法处理ER膜系连的CREBH以产生分泌形式的CREBH;目的2， 阐明CREBH-C与ANGPTL 3/8相互作用调节LPL的调节机制和机制基础 目的3，确定CREBH-C在调节TG分配和整体代谢中的功能意义。 身体代谢和减轻高脂血症和相关的代谢表型。 在资助期内，我们预计将定义一个新的范式，即应激诱导的蛋白质片段， 来源于ER膜蛋白CREBH，可作为一种有效的肝细胞因子调节脂质 体内平衡和全身代谢。揭示了CREBH及其受体的这一前所未有的调控途径， 衍生的肝细胞因子将在控制肝细胞癌的治疗干预中具有重要意义。 高胆固醇血症和相关的代谢和心血管疾病。