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

The Unfolded Protein Response Regulates Hepatic Autophagy by sXBP1-mediated Activation of TFEB. Autophagy. 2020 Jun 28;: Authors: Zhang Z, Qian Q, Li M, Shao F, Ding WX, Lira VA, Chen SX, Sebag SC, Hotamisligil GS, Cao H, Yang L Abstract 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, overexpress...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research