Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism
Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism
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DOI：
10.1038/s41467-019-08591-6
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发表时间：
2019-02-27
影响因子：
16.6
通讯作者：
Ueki, Kohjiro
中科院分区：
文献类型：
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作者：
Sasako, Takayoshi;Ohsugi, Mitsuru;Ueki, Kohjiro
在禁食和进食之间的过渡过程中，肝脏会发生动态的代谢变化。在这里，我们表明，在被Sdf2l1终止摄食后，肝脏中的瞬时内质网应激反应对于正常的糖和脂平衡是必不可少的。Sdf2l1通过与运输蛋白TMED10相互作用来调节ERAD。抑制肝脏中Sdf2l1的表达会导致胰岛素抵抗，并在持续的内质网应激下增加甘油三酯的含量。在肥胖和糖尿病小鼠中，Sdf2l1由于核XBP-1s水平降低而下调，而Sdf2l1表达的恢复缓解了葡萄糖耐量和脂肪肝，并减少了内质网应激。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，未能在肝脏中建立内质网应激反应可能是肥胖相关糖尿病和非酒精性脂肪性肝炎的一个原因，Sdf2l1可以作为治疗的靶点和敏感的生物标志物。
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.