Defective macroautophagy/autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, whether and how unresolved ER stress leads to defects in the autophagy pathway and to the progression of obesity-associated hepatic pathologies remains unclear. Obesity suppresses the expression of hepatic spliced XBP1 (X-box binding protein 1; sXBP1), the key transcription factor that promotes the adaptive UPR. Our RNA-seq analysis revealed that sXBP1 regulates genes involved in lysosomal function in the liver under fasting conditions. Chromatin immunoprecipitation (ChIP) analyses of both primary hepatocytes and whole liver further showed that sXBP1 occupies the -743 to -523 site of the promoter of Tfeb (transcription factor EB), a master regulator of autophagy and lysosome biogenesis. Notably, this occupancy was significantly reduced in livers from patients with steatosis. In mice, hepatic deletion of Xbp1 (xbp1 LKO) suppressed the transcription of Tfeb as well as autophagy, whereas hepatic overexpression of sXbp1 enhanced Tfeb transcription and autophagy. Moreover, overexpression of Tfeb in the xbp1 LKO mouse liver ameliorated glucose intolerance and steatosis in mice with diet-induced obesity (DIO). Conversely, loss of TFEB function impaired the protective role of sXBP1 in hepatic steatosis in mice with DIO. These data indicate that sXBP1-Tfeb signaling has direct functional consequences in the context of obesity. Collectively, our data provide novel insight into how two organelle stress responses are integrated to protect against obesity-associated metabolic dysfunction.

缺陷的巨自噬/自噬和未能响应于内质网（ER）应激而启动适应性未折叠蛋白反应（UPR）均与肥胖相关的代谢功能障碍有关。然而，ER应力是否消除以及如何导致自噬途径缺陷以及与肥胖相关的肝病的进展尚不清楚。肥胖会抑制肝脏剪接的XBP1（X-box结合蛋白1; sXBP1）的表达，XBP是促进适应性UPR的关键转录因子。我们的RNA-seq分析表明，sXBP1在禁食条件下调节肝脏中溶酶体功能的基因。对原代肝细胞和全肝的染色质免疫沉淀（ChIP）分析进一步表明sXBP1占据了启动子的-743至-523位Tfeb（转录因子EB），自噬和溶酶体生物发生的主要调节剂。值得注意的是，脂肪变性患者肝脏中的这种占有率显着降低。在小鼠中，肝脏Xbp1（xbp1 LKO）的缺失抑制了Tfeb的转录以及自噬，而肝脏过表达s Xbp1则增强了Tfeb的转录和自噬。此外，xbp1中Tfeb的过表达LKO小鼠肝脏改善了饮食诱发肥胖症（DIO）小鼠的葡萄糖耐量和脂肪变性。相反，TFEB功能的丧失会损害sXBP1在DIO小鼠肝脂肪变性中的保护作用。这些数据表明，sXBP1- Tfeb信号传导在肥胖的情况下具有直接的功能后果。总体而言，我们的数据为如何整合两个细胞器应激反应以预防与肥胖相关的代谢功能障碍提供了新颖的见解。