Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Division of Endocrinology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
Nat Commun. 2020 Apr 24;11(1):2024. doi: 10.1038/s41467-020-15963-w.
Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.
肝脏和骨骼肌之间的串扰对于葡萄糖稳态至关重要。肝分泌蛋白（hepatokines）是一类在调节肌肉代谢中发挥重要作用的肝脏来源的蛋白质，对于这种通讯至关重要。在这里，我们确定载脂蛋白 J（ApoJ）是一种新型的肝分泌蛋白，通过低密度脂蛋白受体相关蛋白-2（LRP2）依赖性机制靶向肌肉葡萄糖代谢和胰岛素敏感性，同时与胰岛素受体（IR）信号级联反应相关。在肌肉中，LRP2 是胰岛素依赖性 IR 内化所必需的，IR 内化是胰岛素信号的初始触发因素，对于调节下游信号和葡萄糖摄取至关重要。具有生理意义的是，肝脏 ApoJ 或肌肉 LRP2 的缺失会导致胰岛素抵抗和葡萄糖不耐受。在多囊卵巢综合征和胰岛素抵抗患者中，吡格列酮诱导的胰岛素作用改善与肌肉 ApoJ 和 LRP2 表达的增加相关。因此，ApoJ-LRP2 轴是一种新的内分泌回路，是维持正常葡萄糖稳态和胰岛素敏感性的核心。
