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

• 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
• 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

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。 与葡萄糖代谢有关的通讯网络。这个器官间系统的一个关键因素是 现在被称为肝细胞因子，从肝源性蛋白质中鉴定出来，在肝细胞凋亡中起关键作用。 调节骨骼肌的葡萄糖代谢和胰岛素敏感性。载脂蛋白J（apolipoprotienJ，也 称为丛生蛋白）以前没有被怀疑参与葡萄糖稳态的调节 和胰岛素信号。我们的初步数据表明，ApoJ可能作为肝细胞因子发挥作用， 靶向骨骼肌中的胰岛素信号传导和葡萄糖代谢，这可以通过 LRP 1/2（低密度脂蛋白受体相关蛋白-1/2）信号级联。因此我们假设 ApoJ → LRP 1/2轴是一个新的代谢信号网络，对于维持细胞的功能至关重要。 正常的葡萄糖稳态和胰岛素信号，这与胰岛素受体的耦合 系统该提案的总体目标是将ApoJ确定为一种新型肝因子，可控制 通过与胰岛素受体系统偶联的LRP 1/2信号传导实现肌肉葡萄糖稳态。 具体而言，Aim 1将确立ApoJ作为葡萄糖中的新肝细胞因子的生物学功能 新陈代谢. Aim 2将决定ApoJ → LRP 1/2信号通路是否是 胰岛素在骨骼肌中作用。AIM 3将阐明胰岛素增敏的细胞机制， ApoJ的影响为了实现这些目标，我们将使用最先进的技术，包括 条件floxed ApoJ、LRP 1和LRP 2模型以及人类受试者，以阐明代谢 ApoJ → LRP 2轴在器官间通讯网络中的作用这些研究 提供了一个独特的机会，建立一个新的范式，其中ApoJ → LRP 2信号网络 是葡萄糖稳态的关键决定因素，可能为治疗肥胖提供新的靶点 和糖尿病

项目成果

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

TET2: Is a potential gatekeeper for the action of thiazolidinedione in fat cells?

TET2：噻唑烷二酮在脂肪细胞中的作用是否是潜在的看门人？

• DOI: 10.1016/j.metabol.2018.10.001
• 发表时间: 2018
• 期刊: Metabolism: clinical and experimental
• 作者: Seo,JiA;Kim,Young-Bum
• 通讯作者: Kim,Young-Bum