A novel CREBH-derived hepatokine regulates triglyceride metabolism

项目摘要：高甘油三酯血症是一种血液甘油三酯(TG)水平升高的情况，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。血浆甘油三酯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，经内皮细胞转运至毛细血管腔 转运体GPIHBP1，在那里它水解血浆甘油三酯，使其局部摄取到周围组织。虽然意义重大 已取得进展，LPL活性的微调调节以及甘油三酯的脂解和分配 外周组织有待进一步阐明。 在上一个资金周期中，我们揭示了内质网(ER)-栓系的、富含肝脏的 转录因子CREBH作为一种昼夜代谢调节因子，将昼夜节律调节整合到 能量平衡。最近，我们发现CREBH的C-末端片段(CREBH-C)，产生了 通过调节的膜内蛋白分解(RIP)，作为一种“肝因子”从肝脏分泌到循环中。 根据能源需求。分泌的CREBH-C与血管生成素样3(Angptl3)和ANGPTL8相互作用 阻止Angptl3/8与LPL之间的相互抑制作用，从而促进LPL活性和TG分配 进入外周组织。循环CREBH-C促进甘油三酯清除和分配并缓解 由过度营养引起的高甘油三酯血症。这些证据促使我们假设内质网 膜拴CREBH被RIP处理以产生一种新的肝细胞因子CREBH-C，它与 ANGPTLS调节血管内LPL活性、甘油三酯在周围组织和全身的分配 新陈代谢。CREBH-C干预可增加代谢灵活性，从而缓解高甘油三酯血症和 与之相关的代谢紊乱。在这一应用中，我们将利用分子和细胞方法，遗传 动物模型，以及创新的LPL监测和血脂追踪方法，以定义一种新的肝素， CREBH-C及其在LPL活性和甘油三酯稳态中的调节作用：目的1，确定机制途径 用来加工ER膜系留的CREBH以产生分泌型CREBH；目标2，至 CREBH-C与Angptl3/8相互作用调节LPL的调控及机制基础 目的3，确定CREBH-C在调节甘油三酯分配和整体-甘油三酯合成中的功能意义。 在身体代谢和减轻高甘油三酯血症和相关的代谢表型。 在资助期内，我们预计将定义一种新的范式，即一种压力诱导的蛋白质片段， 来源于ER膜蛋白CREBH，可作为一种强大的肝细胞因子发挥调节血脂的作用 动态平衡和全身代谢。揭示CREBH及其相关基因史无前例的调控途径 衍生性肝细胞因子在控制血吸虫病的治疗干预中将有重要意义 高甘油三酯血症及相关的代谢和心血管疾病。

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.