Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, 113-8655, Japan.
Nat Commun. 2019 Feb 27;10(1):947. doi: 10.1038/s41467-019-08591-6.
Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.
在禁食和进食之间，肝脏会发生动态代谢变化。在这里，我们发现进食终止后肝内质网应激反应是 Sdf2l1 维持正常血糖和脂质稳态所必需的。Sdf2l1 通过与一种运输蛋白 TMED10 相互作用来调节 ERAD。肝脏中 Sdf2l1 表达的抑制会导致胰岛素抵抗，并伴有持续的内质网应激增加甘油三酯含量。在肥胖和糖尿病小鼠中，由于核 XBP-1s 水平降低，Sdf2l1 的表达下调，而 Sdf2l1 表达的恢复则可改善葡萄糖不耐受和脂肪肝，同时降低内质网应激。在糖尿病患者中，Sdf2l1 诱导不足与胰岛素抵抗和脂肪性肝炎的进展相关。因此，肝脏内质网应激反应的缺失可能是肥胖相关糖尿病和非酒精性脂肪性肝炎的一个因果因素，Sdf2l1 可以作为一种治疗靶点和敏感的生物标志物。
