ApoJ as a novel hepatokine targeting muscle glucose metabolism

ApoJ 作为一种靶向肌肉葡萄糖代谢的新型肝因子

基本信息

批准号：
9978058
负责人：
YOUNG-BUM KIM
金额：
$ 43.25万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978058
关键词：
Area Biological Process Cell membrane Communication Complex Coupled Couples Data Diabetes Mellitus Endocytosis Fasting Glucose Intolerance Goals Grant Hepatic Human Impairment Insulin Insulin Receptor Insulin Resistance LDL-Receptor Related Protein 1 LDL-Receptor Related Protein 2 Lead Link Liver LoxP-flanked allele Maintenance Mediating Metabolic Metabolic Diseases Modeling Molecular Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Pathogenesis Physiological Physiology Play Proteins Risk Factors Role Serum Signal Pathway Signal Transduction Skeletal Muscle System Technology Tissues Type 2 diabetic blood glucose regulation experimental study glucose disposal glucose metabolism glucose transport human subject insulin regulation insulin sensitivity insulin sensitizing drugs insulin signaling interest liver function metabolic phenotype new therapeutic target novel obesity treatment receptor sulfated glycoprotein 2

项目摘要

A major challenge in the field of metabolic physiology has been to understand the interorgan communication networks linking to glucose metabolism. One critical factor for this interorgan system is now known as hepatokines, identified from liver-derived proteins, and that play a pivotal role in regulating glucose metabolism and insulin sensitivity in skeletal muscle. ApoJ (apolipoprotienJ, also called clusterin) was not previously suspected to be involved in the regulation of glucose homeostasis and insulin signaling. Our preliminary data demonstrate that ApoJ may function as a hepatokine targeting insulin signaling and glucose metabolism in skeletal muscle, which could be mediated via the LRP1/2 (low-density lipoprotein receptor-related protein-1/2) signaling cascade. We thus hypothesize that the ApoJ → LRP1/2 axis is a novel metabolic signaling network that is crucial for the maintenance of normal glucose homeostasis and insulin signaling and that this couples with the insulin receptor system. The overall objective of this proposal is to identify ApoJ as a novel hepatokine that controls muscle glucose homeostasis via LRP1/2 signaling coupled with the insulin receptor system. Specifically, Aim1 will establish the biological function of ApoJ as a new hepatokine in glucose metabolism. Aim2 will determine whether the ApoJ → LRP1/2 signaling pathway is a key component of insulin action in skeletal muscle. Aim3 will elucidate the cellular mechanisms for the insulin-sensitizing effects of ApoJ. To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ, LRP1 and LRP2 models as well as human subjects to clarify the metabolic function of the ApoJ → LRP2 axis in the context of interorgan communication networks. These studies provide a unique opportunity to establish a new paradigm in which the ApoJ → LRP2 signaling network is a key determinant of glucose homeostasis, and may offer a novel target for the treatment of obesity and diabetes.

代谢生理学领域的一个主要挑战是了解器官间的相互作用与葡萄糖代谢相关的通讯网络是这一器官间系统的一个关键因素。现在被称为肝因子，从肝脏衍生的蛋白质中鉴定出来，在调节骨骼肌中的葡萄糖代谢和胰岛素敏感性。称为簇蛋白）之前并未被怀疑参与葡萄糖稳态的调节我们的初步数据表明 ApoJ 可能充当肝因子。针对骨骼肌中的胰岛素信号和葡萄糖代谢，这可以通过 LRP1/2（低密度脂蛋白受体相关蛋白-1/2）信号级联。 ApoJ → LRP1/2 轴是一种新型代谢信号网络，对于维持正常的葡萄糖稳态和胰岛素信号传导，并且与胰岛素受体结合该系统的总体目标是将 ApoJ 确定为一种新型的控制肝因子。通过 LRP1/2 信号传导与胰岛素受体系统耦合来维持肌肉葡萄糖稳态。具体来说，Aim1将确立ApoJ作为葡萄糖中新肝因子的生物学功能 Aim2将决定ApoJ→LRP1/2信号通路是否为关键组成部分。骨骼肌中的胰岛素作用将阐明胰岛素敏化的细胞机制。为了实现这些目标，我们将使用最先进的技术，包括有条件的 floxed ApoJ、LRP1 和 LRP2 模型以及人类受试者，以阐明代谢 ApoJ → LRP2 轴在器官间通讯网络中的功能。提供了建立新范例的独特机会，其中 ApoJ → LRP2 信号网络是葡萄糖稳态的关键决定因素，可能为肥胖症的治疗提供新的靶点和糖尿病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Urine clusterin/apolipoprotein J is linked to tubular damage and renal outcomes in patients with type 2 diabetes mellitus.

DOI：
10.1111/cen.13360
发表时间：
2017-08
期刊：
Clinical endocrinology
影响因子：
3.2
作者：
Kim SS;Song SH;Kim JH;Jeon YK;Kim BH;Kang MC;Chun SW;Hong SH;Chung M;Kim YK;Kim IJ;Kim YB
通讯作者：
Kim YB

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