The Unfolded Protein Response Regulates Hepatic Autophagy by sXBP1-mediated Activation of TFEB

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 <i>Tfeb</i> (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 <i>Xbp1</i> (<i>xbp1</i> LKO) suppressed the transcription of <i>Tfeb</i> as well as autophagy, whereas hepatic overexpression of s<i>Xbp1</i> enhanced <i>Tfeb</i> transcription and autophagy. Moreover, overexpression of <i>Tfeb</i> in the <i>xbp1</i> 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-<i>Tfeb</i> 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.