ApoJ as a novel hepatokine targeting muscle glucose metabolism

新陈代谢生理学领域的一个主要挑战是理解器官间的 与葡萄糖代谢相关的通讯网络。这种器官间系统的一个关键因素是 现在被称为肝素，从肝脏衍生的蛋白质中鉴定出来，并在 调节骨骼肌糖代谢和胰岛素敏感性。ApoJ(载脂蛋白J，也称apoJ 称为聚集素)之前并未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，载脂蛋白J可能是一种肝细胞因子 靶向胰岛素信号和骨骼肌中的葡萄糖代谢，这可能通过 LRP1/2(低密度脂蛋白受体相关蛋白-1/2)信号转导通路。因此，我们假设 ApoJ→LRP1/2轴是一个新的代谢信号网络，对维持 正常血糖稳态和胰岛素信号转导，并与胰岛素受体偶联 系统。这项提议的总体目标是确定载脂蛋白J是一种新的肝素，它可以控制 通过LRP1/2信号和胰岛素受体系统实现的肌肉葡萄糖动态平衡。 具体地说，Aim1将确立ApoJ作为葡萄糖中一种新的肝细胞因子的生物学功能 新陈代谢。AIM2将确定ApoJ→LRP1/2信号通路是否是 胰岛素在骨骼肌中的作用。Aim3将阐明胰岛素增敏的细胞机制。 ApoJ的影响。为了达到这些目标，我们将使用最先进的技术，包括 条件漂浮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。这些研究 为建立一种新的范式提供了独特的机会，在这种新范式中，ApoJ→LRP2信令网络 是葡萄糖稳态的关键决定因素，可能为肥胖的治疗提供一个新的靶点。 还有糖尿病。

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.